BACKGROUND
transcription factors  are protein complexes responsible for the recruitment of basic transcription machinery to dna  <cit> .
at the molecular level, gene regulation is achieved via the binding of tfs to dna but increases in complexity at a cellular level.
distinct transcriptional programs made of interacting networks of tfs each regulating a subset of genes work cooperatively to generate the diversity of cells seen in multicellular organisms.
mapping of tf interactions within such net- works are important for understanding of their control over gene expression and higher order functions such as cell fate determination  <cit> .
although cell type specific expression of tfs have been identified, it is through combinatorial binding with partner tfs that the recruitment and formation of preinitiation complexes and rna polymerases required for the transcription of cell type specific genes is achieved.
identification of such unique combinatory tf binding patterns occurring in a cell type specific manner is necessary for understanding of the unique transcriptional programmes which givejk rise to the repertoire of cell types seen in a multicellular organism  <cit> .
cell type agnostic interactions do exist between tfs and are tf specific where master regulator tfs like the signal transducer and activator of transcription  bind with its cofactors to activate transcription of gene targets regardless of cell types  <cit> .
while existing methods of discovering tf-cofactor interactions require protein interaction assays, such as protein complex immunoprecipitation, or two hybrid screens which are low throughput, costly and non-indicative of in vivo conditions  <cit> .
specificity of tfs to their cognate binding sites have been well studied and with chip-sequencing  for chromatin immunoprecipitation  coupled to ultra-high throughput massively parallel sequencing  <cit> .
during chip-seq, dna binding proteins are treated with a fixative agent, usually formaldehyde, and cross-linked to their bound dna before it is extracted and the chromatin sheared to a size of 100- <dig> bp  <cit> .
the resulting protein of interest in this case tfs are immunoenriched using an antibody precipitation targeted at the tf.
thereafter, the cross-links are reversed and the dna purified and analysed by high-throughput dna sequencing.
regions within the genome significantly mapped back onto are identified as potential protein-dna interaction sites or peaks  <cit> .
sequenced regions include those bound by cofactors is largely due to the fixation step during chip where fixation not only occurs between the antibody targeted tfs and bound region but similarly with cofactors in a tfbs-tf-cofactor-tfbs manner  <cit> .
as a result, protein-dna interaction sites sequenced are not exclusive to the targeted tfs but also of their cofactors.
although, this has generally been viewed as noise and an artefact of the chip method impeding discovery of canonical tfbs motifs belonging to the targeted tf, documentation and support of enrichment of cofactor bound regions have been reported ranging from areas concerning peak calling techniques to genome-wide binding studies  <cit> .
thus, identification and scanning of bound genomic regions by the chip targeted tfs and cofactors in vivo for transcription factor binding sites  can be achieved and their co-occurrences used as a proxy for their interactions.
while analysis of tf chip-seq peaks data is much more scalable for investigating far larger libraries of tfs.
given the existence of cell type and tf specific tf-cofactor interactions as well as the challenges in conventional methods of tf-cofactor discovery, we set out to explore in silico alternatives to analysing cell type and tf specific tf-cofactor interactions from tfbs motif enrichments within chip-seq peaks.
for cell type specific enrichments, we screened peaks for enrichments in non-canonical motifs, motifs with no known associations with the immuno-targeted tfs, across mutliple cell types .
whereas for tf specific enrichments >20% again in non-canonical motifs in >  <dig> cell types targeting the same tf.
in our study we used human chip-seq data from the encyclopedia of dna elements  project  <cit> .
in the june  <dig> release by encode, the encode transcription factor super regulation track integrates previously separate tracks containing chip-seq datasets from  <dig> experiments onto a single dataset which is mapped onto the latest human genome assembly .
the release includes chip-seq experiments belonging to a variety of tfs carried out using different cell types.
in contrast to previous reports of cofactor sig-natures within tf chip-seq peak data  <cit>  for our analysis, to our knowledge is the largest, spanning  <dig> chip-seq datasets after filtering.
for this study, we aim to identify tf-cofactor interaction networks through careful screening and analysis of transcription cofactor motifs captured by tf chip-seq as well as uncover nuances in their interaction specificities relating to cell types, and individual tfs.
RESULTS
in the following, we begin with an overview of analyses conducted on the chip-seq dataset as well as report significant co-occurring tfbs motifs belonging to both validated and predicted cofactors.
of these, some exhibit cell type as well as tf specificity upon applying criteria specific filters.
overview
using encode's recent release, a total of  <dig> chip-seq experiments studying  <dig> tfs in  <dig> different cell cultures were considered initially for this study totaling  <dig> , <dig> unique chip-seq peaks.
we removed experiments investigating basic transcription machinery polymerase i, ii and iii and non-canonical tf ctcf.
peaks belonging to high occupancy regions, that is being ubiquitous across chip-seq experiments regardless of conditions were also not considered.
finally, tfs investigated in only a single cell type as well as those without matched dna binding site motifs were also removed.
also excluded from analysis were peaks showing extensive overlaps with peaks of other tf chip-seq experiments targeting different tfs .
accumulation of functionally unrelated dna binding factors in regions known as 'high-occupancy target'  regions have been documented  <cit> .
nucleation at these sites has been shown mainly to be a result of protein-protein interactions  <cit>  while protein-dna interactions if any are still unclear hence, excluded.
the resulting dataset containing  <dig> , <dig> peaks from  <dig> unique chip-seq experiments across  <dig> unique cell cultures of various tissue types was chosen.
<dig> unique tfs remained after curation with a total of  <dig> mapped canonical tfbs motif position weight matrix .
finally, we looked for cell type specific as well as tf specific co-occurrences and identified a total of  <dig> such motifs .
examples of the above will be discussed in the following.
all identified co-occurring motifs and potential factors are provided in the supplementary .
listed in the table are motifs found consistently enriched within chip-seq peaks investigating a particular cell type independent of the tf targeted by the chip process.
listed in the table are motifs found consistently enriched within chip-seq peaks investigating a particular tf independent of the cell type investigated.
proximally and distally located co-occurring motifs
peaks were later classified based on presence of canonical tfbs motifs belonging to the chip targeted tf  and a total of  <dig>  non-canonical motifs were identified.
co-occurring motifs identified within peaks present and absent for the targeted tf's canonical motifs are thus classified as proximal and distal .
co-occurrence specificity of motifs
to identify tf-cofactor networks operating proximally and distally through cis- and trans-acting elements with respect to the chip targeted tfs, we searched for enrichments in co-occurring tfbs motifs within chip-seq peaks.
we based our search on three parameters namely:  motif abundance; the enrichment of the co-occurring motif in the chip-seq peaks,  motif ubiquity; the presence of the co-occurring motif across peaks from different tf chip-seq experiments and the  uniqueness or dis-similarity the targeted tf's canonical motif using similarity scores with p-values <  <dig> .
potentially novel as well as known tf-cofactor pairs have been identified and selected examples will be discussed in the following.
for the complete list of co-occurring motifs identified please refer to the supplementary tables provided .
hepatocyte specific tf: hnf4α
the most striking cell type specific enrichment observed belonged to the motif of hepatocyte nuclear factor  <dig> alpha   <cit> .
the motif was found to be enriched both proximally and distally from chip targeted tf motifs found within the hepg <dig> cell lines regardless of the chip targeted tfs but not in other cell types .
hnf4α belongs to the superfamily of nuclear receptors known to be expressed endogenously in adult liver cell lines.
functionally, hnf4α is a ligand-dependent transcription factor which is a master regulator for liver-specific gene expression and forms homodimers as well as heterodimers with other tfs via its af- <dig> transactivation domain  <cit> .
co-occurring with hnf4α motifs are the canonical motifs of  <dig> cofactor tfs  both proximally and distally located peaks.
more cell type specific co-occuring tf motifs can be found in additional file  <dig>
tf specific co-occurring motifs
as in the earlier section, we selected co-occurring motifs fulfilling the specific criteria of motif enrichment  across >  <dig> cell types targeting the same tf.
<dig> tf specific motifs were identified with the majority  proximal to target tfbs motifs.
of these are experimentally verified co-factors of the target tfs as well as those whose identity as a co-factor has not been experimentally verified .
in the following we will discuss briefly  <dig> examples of such motifs showing tf specific enrichment .
examples of known associations
signal transducer and activator of transcription  <dig> and activator protein-1
upon applying the screening process, five tfbs motifs where found to be enriched proximally with canonical tfbs motifs of the signal transducer and activator of transcription three   regardless of cell type but not so in experiments targeting other tfs .
four out of five of these belonged to known cofactors and homologues of stat <dig>
three of the motifs identified were found to be canonical motifs of known stat <dig> cofactor, activator protein  <dig>   and its subunits c-fos and c-jun .
associations between stat <dig> and ap- <dig> complexes are well characterised and their binding site motifs known to co-occur proximally together  <cit> .
in addition, numerous assays con-ducted confirms their interactions both in vitro and in vivo  <cit> .
ap- <dig> and stat <dig> are known to be responsible for regulating the expression of genes mediating tissue repair and regeneration ubiquitously across cell types.
the co-occurrences in the two's tfbs motifs in a cell type independent manner therefore is not surprising.
of the remaining two motifs, one is a saccharomyces cerevisiae homologue of the ap- <dig> sub-unit c-jun, gcn <dig>  which binds to the ap- <dig> specific sequences   <cit> .
the other is a yeast tf responsible for regulating arginine-responsive genes  <cit> .
specificity protein  <dig>  in a separate example of a tf specific co-occurrence of tfbs motifs, we observed the enrichment of 'ccaat' family of tfs namely nfy, and the saccharomyces cerevisiae homologues hap <dig>  hap <dig> and hap <dig>  in proximal peaks of chip-seq experiments targeting sp <dig> across cell types .
it has been documented that sp <dig> and nfy share large overlaps in promoter occupancies across numerous genes  <cit>  as well as functional assays testing for co-operativity between the two  <cit> .
the positive identification of ap- <dig> and its subunits' motifs in chip-seq peaks studying to stat <dig> but not in peaks studying sp <dig> and vis versa acts simultaneously as a positive internal control as well as a negative internal control for this study.
example novel cofactors
nfκb and ebf1
tf specific motif co-occurrences identified in our analysis which have not been experimentally validated to our knowledge previously as a cofactors belong to ebf <dig> .
the co-occurrence was observed in the proximal peaks of chip-seq targeting nfκb  and the enrichment is fairly uniform across lymphocytes, embryonic stem cells, hepatocytes and human leukemia cells as shown in figure  <dig>
ebf <dig> has been found to be important in the regulation of genes responsible for the normal progression of b cell development.
similarly, nfκb too has been shown to be essential for proper b cell development  <cit> .
hence, the possibility of the two participating in some form of co-operative binding to regulate b cell development genes is high.
plagl <dig> and c-myc
the motif of plagl <dig>  was found enriched within peaks from chip-seq experiments targeting c-myc across cervix adenocarcinoma cells , human leukemia cells , hepatocytes , human breast adenocarcinoma cells , lymophocytes  and promyelocytic cells .
plagl <dig> and c-myc are known regulators of the cell cycle and plagl <dig> have been associated with inducing cell cycle arrest and apoptosis  <cit>  while c-myc involved in cell proliferation and apoptosis  <cit> .
it is still unclear if the two tfs are true cofactors and will be a potential target for verification experimentally.
in addition, the motif of plagl <dig> was also identified in the peaks targeting sp <dig> and it is known that plagl <dig> binds with sp <dig> response elements  <cit> .
a summary figure showing the enrichment of the above mentioned pairing can be found in figure  <dig>
CONCLUSIONS
our analyses have uncovered enrichments of known and novel tf cofactors combinations occurring in cell-type and tf specific manner worth investigating.
through the examples discussed we've shown the retrieval of  <dig> verified cofactors including hnf4a in hepatocytes, stat <dig> and ap- <dig>  and nfy-a and sp <dig> as well as novel co-occurrences such as ebf <dig> and nfkb suggesting the possibility of the two being cofactors.
thus, it is apparent following critical examination of enrichments in non-canonical tfbs motifs in chip-seq data that cofactor motifs signatures are indeed detectable and retrievable through rigorous screening as described in our study.
in conclusion, we have shown through careful examination of motif enrichment in chip-seq data that not only are global cofactors of tfs be identified but also criteria specific binding partners.
this could potentially be used for quick identification of potential cofactors of newly characterised tfs not only in humans but also other model organisms.
such analyses as described in our study will prove be invaluable as more tfs are interrogated using chip-seq as the cost of next generation sequencing continues to become more affordable.

 transcription factors are protein complexes responsible for the recruitment of basic transcription machinery to dna. at the molecular level, gene regulation is achieved via the binding of tfs to dna but increases in complexity at a cellular level. distinct transcriptional programs made of interacting networks of tfs each regulating a subset of genes work cooperatively to generate the diversity of cells seen in multicellular organisms. mapping of tf interactions within such net- works are important for understanding of their control over gene expression and higher order functions such as cell fate determination. although cell type specific expression of tfs have been identified, it is through combinatorial binding with partner tfs that the recruitment and formation of preinitiation complexes and rna polymerases required for the transcription of cell type specific genes is achieved. identification of such unique combinatory tf binding patterns occurring in a cell type specific manner is necessary for understanding of the unique transcriptional programmes which givejk rise to the repertoire of cell types seen in a multicellular organism. cell type agnostic interactions do exist between tfs and are tf specific where master regulator tfs like the signal transducer and activator of transcription bind with its cofactors to activate transcription of gene targets regardless of cell types. while existing methods of discovering tf-cofactor interactions require protein interaction assays, such as protein complex immunoprecipitation, or two hybrid screens which are low throughput, costly and non-indicative of in vivo conditions. specificity of tfs to their cognate binding sites have been well studied and with chip-sequencing for chromatin immunoprecipitation coupled to ultra-high throughput massively parallel sequencing. during chip-seq, dna binding proteins are treated with a fixative agent, usually formaldehyde, and cross-linked to their bound dna before it is extracted and the chromatin sheared to a size of 100- bp. the resulting protein of interest in this case tfs are immunoenriched using an antibody precipitation targeted at the tf. thereafter, the cross-links are reversed and the dna purified and analysed by high-throughput dna sequencing. regions within the genome significantly mapped back onto are identified as potential protein-dna interaction sites or peaks. sequenced regions include those bound by cofactors is largely due to the fixation step during chip where fixation not only occurs between the antibody targeted tfs and bound region but similarly with cofactors in a tfbs-tf-cofactor-tfbs manner. as a result, protein-dna interaction sites sequenced are not exclusive to the targeted tfs but also of their cofactors. although, this has generally been viewed as noise and an artefact of the chip method impeding discovery of canonical tfbs motifs belonging to the targeted tf, documentation and support of enrichment of cofactor bound regions have been reported ranging from areas concerning peak calling techniques to genome-wide binding studies. thus, identification and scanning of bound genomic regions by the chip targeted tfs and cofactors in vivo for transcription factor binding sites can be achieved and their co-occurrences used as a proxy for their interactions. while analysis of tf chip-seq peaks data is much more scalable for investigating far larger libraries of tfs. given the existence of cell type and tf specific tf-cofactor interactions as well as the challenges in conventional methods of tf-cofactor discovery, we set out to explore in silico alternatives to analysing cell type and tf specific tf-cofactor interactions from tfbs motif enrichments within chip-seq peaks. for cell type specific enrichments, we screened peaks for enrichments in non-canonical motifs, motifs with no known associations with the immuno-targeted tfs, across mutliple cell types. whereas for tf specific enrichments >20% again in non-canonical motifs in > cell types targeting the same tf. in our study we used human chip-seq data from the encyclopedia of dna elements project. in the june release by encode, the encode transcription factor super regulation track integrates previously separate tracks containing chip-seq datasets from experiments onto a single dataset which is mapped onto the latest human genome assembly. the release includes chip-seq experiments belonging to a variety of tfs carried out using different cell types. in contrast to previous reports of cofactor sig-natures within tf chip-seq peak data for our analysis, to our knowledge is the largest, spanning chip-seq datasets after filtering. for this study, we aim to identify tf-cofactor interaction networks through careful screening and analysis of transcription cofactor motifs captured by tf chip-seq as well as uncover nuances in their interaction specificities relating to cell types, and individual tfs.  in the following, we begin with an overview of analyses conducted on the chip-seq dataset as well as report significant co-occurring tfbs motifs belonging to both validated and predicted cofactors. of these, some exhibit cell type as well as tf specificity upon applying criteria specific filters. overview using encode's recent release, a total of chip-seq experiments studying tfs in different cell cultures were considered initially for this study totaling, unique chip-seq peaks. we removed experiments investigating basic transcription machinery polymerase i, ii and iii and non-canonical tf ctcf. peaks belonging to high occupancy regions, that is being ubiquitous across chip-seq experiments regardless of conditions were also not considered. finally, tfs investigated in only a single cell type as well as those without matched dna binding site motifs were also removed. also excluded from analysis were peaks showing extensive overlaps with peaks of other tf chip-seq experiments targeting different tfs. accumulation of functionally unrelated dna binding factors in regions known as'high-occupancy target' regions have been documented. nucleation at these sites has been shown mainly to be a result of protein-protein interactions while protein-dna interactions if any are still unclear hence, excluded. the resulting dataset containing, peaks from unique chip-seq experiments across unique cell cultures of various tissue types was chosen. unique tfs remained after curation with a total of mapped canonical tfbs motif position weight matrix. finally, we looked for cell type specific as well as tf specific co-occurrences and identified a total of such motifs. examples of the above will be discussed in the following. all identified co-occurring motifs and potential factors are provided in the supplementary. listed in the table are motifs found consistently enriched within chip-seq peaks investigating a particular cell type independent of the tf targeted by the chip process. listed in the table are motifs found consistently enriched within chip-seq peaks investigating a particular tf independent of the cell type investigated. proximally and distally located co-occurring motifs peaks were later classified based on presence of canonical tfbs motifs belonging to the chip targeted tf and a total of non-canonical motifs were identified. co-occurring motifs identified within peaks present and absent for the targeted tf's canonical motifs are thus classified as proximal and distal. co-occurrence specificity of motifs to identify tf-cofactor networks operating proximally and distally through cis- and trans-acting elements with respect to the chip targeted tfs, we searched for enrichments in co-occurring tfbs motifs within chip-seq peaks. we based our search on three parameters namely: motif abundance; the enrichment of the co-occurring motif in the chip-seq peaks, motif ubiquity; the presence of the co-occurring motif across peaks from different tf chip-seq experiments and the uniqueness or dis-similarity the targeted tf's canonical motif using similarity scores with p-values <. potentially novel as well as known tf-cofactor pairs have been identified and selected examples will be discussed in the following. for the complete list of co-occurring motifs identified please refer to the supplementary tables provided. hepatocyte specific tf: hnf4α the most striking cell type specific enrichment observed belonged to the motif of hepatocyte nuclear factor alpha. the motif was found to be enriched both proximally and distally from chip targeted tf motifs found within the hepg cell lines regardless of the chip targeted tfs but not in other cell types. hnf4α belongs to the superfamily of nuclear receptors known to be expressed endogenously in adult liver cell lines. functionally, hnf4α is a ligand-dependent transcription factor which is a master regulator for liver-specific gene expression and forms homodimers as well as heterodimers with other tfs via its af- transactivation domain. co-occurring with hnf4α motifs are the canonical motifs of cofactor tfs both proximally and distally located peaks. more cell type specific co-occuring tf motifs can be found in additional file tf specific co-occurring motifs as in the earlier section, we selected co-occurring motifs fulfilling the specific criteria of motif enrichment across > cell types targeting the same tf. tf specific motifs were identified with the majority proximal to target tfbs motifs. of these are experimentally verified co-factors of the target tfs as well as those whose identity as a co-factor has not been experimentally verified. in the following we will discuss briefly examples of such motifs showing tf specific enrichment. examples of known associations signal transducer and activator of transcription and activator protein-1 upon applying the screening process, five tfbs motifs where found to be enriched proximally with canonical tfbs motifs of the signal transducer and activator of transcription three regardless of cell type but not so in experiments targeting other tfs. four out of five of these belonged to known cofactors and homologues of stat three of the motifs identified were found to be canonical motifs of known stat cofactor, activator protein and its subunits c-fos and c-jun. associations between stat and ap- complexes are well characterised and their binding site motifs known to co-occur proximally together. in addition, numerous assays con-ducted confirms their interactions both in vitro and in vivo. ap- and stat are known to be responsible for regulating the expression of genes mediating tissue repair and regeneration ubiquitously across cell types. the co-occurrences in the two's tfbs motifs in a cell type independent manner therefore is not surprising. of the remaining two motifs, one is a saccharomyces cerevisiae homologue of the ap- sub-unit c-jun, gcn which binds to the ap- specific sequences. the other is a yeast tf responsible for regulating arginine-responsive genes. specificity protein in a separate example of a tf specific co-occurrence of tfbs motifs, we observed the enrichment of'ccaat' family of tfs namely nfy, and the saccharomyces cerevisiae homologues hap hap and hap in proximal peaks of chip-seq experiments targeting sp across cell types. it has been documented that sp and nfy share large overlaps in promoter occupancies across numerous genes as well as functional assays testing for co-operativity between the two. the positive identification of ap- and its subunits' motifs in chip-seq peaks studying to stat but not in peaks studying sp and vis versa acts simultaneously as a positive internal control as well as a negative internal control for this study. example novel cofactors nfκb and ebf1 tf specific motif co-occurrences identified in our analysis which have not been experimentally validated to our knowledge previously as a cofactors belong to ebf. the co-occurrence was observed in the proximal peaks of chip-seq targeting nfκb and the enrichment is fairly uniform across lymphocytes, embryonic stem cells, hepatocytes and human leukemia cells as shown in figure ebf has been found to be important in the regulation of genes responsible for the normal progression of b cell development. similarly, nfκb too has been shown to be essential for proper b cell development. hence, the possibility of the two participating in some form of co-operative binding to regulate b cell development genes is high. plagl and c-myc the motif of plagl was found enriched within peaks from chip-seq experiments targeting c-myc across cervix adenocarcinoma cells, human leukemia cells, hepatocytes, human breast adenocarcinoma cells, lymophocytes and promyelocytic cells. plagl and c-myc are known regulators of the cell cycle and plagl have been associated with inducing cell cycle arrest and apoptosis while c-myc involved in cell proliferation and apoptosis. it is still unclear if the two tfs are true cofactors and will be a potential target for verification experimentally. in addition, the motif of plagl was also identified in the peaks targeting sp and it is known that plagl binds with sp response elements. a summary figure showing the enrichment of the above mentioned pairing can be found in figure  our analyses have uncovered enrichments of known and novel tf cofactors combinations occurring in cell-type and tf specific manner worth investigating. through the examples discussed we've shown the retrieval of verified cofactors including hnf4a in hepatocytes, stat and ap- and nfy-a and sp as well as novel co-occurrences such as ebf and nfkb suggesting the possibility of the two being cofactors. thus, it is apparent following critical examination of enrichments in non-canonical tfbs motifs in chip-seq data that cofactor motifs signatures are indeed detectable and retrievable through rigorous screening as described in our study. in conclusion, we have shown through careful examination of motif enrichment in chip-seq data that not only are global cofactors of tfs be identified but also criteria specific binding partners. this could potentially be used for quick identification of potential cofactors of newly characterised tfs not only in humans but also other model organisms. such analyses as described in our study will prove be invaluable as more tfs are interrogated using chip-seq as the cost of next generation sequencing continues to become more affordable. 
using tf targeted chromatin immunoprecipitation coupled with massively parallel sequencing data from encyclopedia of dna elements, we report cell type and tf specific tf-cofactor interactions captured in vivo through enrichments of non target cofactor binding site motifs within chip-seq peaks. cell type and tf specific interactions between transcription factors and cofactors are essential for transcriptional regulation through recruitment of general transcription machinery to gene promoter regions and their identification heavily reliant on protein interaction assays. novel cofactor binding site enrichments observed provides valuable insight into tf and cell type specific interactions driving tf interactions. here we present the findings to our analyses surrounding the investigation of tf-cofactor interactions encoded within tf chip-seq peaks.
 cell type and tf specific interactions between transcription factors and cofactors are essential for transcriptional regulation through recruitment of general transcription machinery to gene promoter regions and their identification heavily reliant on protein interaction assays.  using tf targeted chromatin immunoprecipitation coupled with massively parallel sequencing data from encyclopedia of dna elements, we report cell type and tf specific tf-cofactor interactions captured in vivo through enrichments of non target cofactor binding site motifs within chip-seq peaks. we observe enrichments in both known and novel cofactor motifs.  given the regulatory implications which tf and cofactor interactions have on a cell's phenotype, their identification is necessary but challenging. here we present the findings to our analyses surrounding the investigation of tf-cofactor interactions encoded within tf chip-seq peaks. novel cofactor binding site enrichments observed provides valuable insight into tf and cell type specific interactions driving tf interactions. 20- september asia pacific bioinformatics network twelfth international conference on bioinformatics taicang, china 