Hansel, Gretel, and the Consequences of Failing to Remove Histone Methylation Breadcrumbs
Authors: Teresa W. Lee, David J. Katz
Journal: Trends in Genetics (2020)

The breadcrumb model: like a trail of breadcrumbs, histone methylation is added cotranscriptionally to retain a memory of prior gene expression.The inappropriate retention of histone methylation has developmental consequences during certain cell fate transitions, like immediately after fertilization or during stem cell differentiation.Transcriptional memory may need to be continuously suppressed, even in terminally differentiated cells.The two-hit hypothesis of epigenetic reprogramming: weak heterozygous mutations in histone-modifying enzymes combine with a second environmental or genetic defect during vulnerable developmental time points to compromise epigenetic reprogramming. Like breadcrumbs in the forest, cotranscriptionally acquired histone methylation acts as a memory of prior transcription. Because it can be retained through cell divisions, transcriptional memory allows cells to coordinate complex transcriptional programs during development. However, if not reprogrammed properly during cell fate transitions, it can also disrupt cellular identity. In this review, we discuss the consequences of failure to reprogram histone methylation during three crucial epigenetic reprogramming windows: maternal reprogramming at fertilization, embryonic stem cell (ESC) differentiation, and the continuous maintenance of cell identity in differentiated cells. In addition, we discuss how following the wrong breadcrumb trail of transcriptional memory provides a framework for understanding how heterozygous loss-of-function mutations in histone-modifying enzymes may cause severe neurodevelopmental disorders. Like breadcrumbs in the forest, cotranscriptionally acquired histone methylation acts as a memory of prior transcription. Because it can be retained through cell divisions, transcriptional memory allows cells to coordinate complex transcriptional programs during development. However, if not reprogrammed properly during cell fate transitions, it can also disrupt cellular identity. In this review, we discuss the consequences of failure to reprogram histone methylation during three crucial epigenetic reprogramming windows: maternal reprogramming at fertilization, embryonic stem cell (ESC) differentiation, and the continuous maintenance of cell identity in differentiated cells. In addition, we discuss how following the wrong breadcrumb trail of transcriptional memory provides a framework for understanding how heterozygous loss-of-function mutations in histone-modifying enzymes may cause severe neurodevelopmental disorders. The genome is packaged as chromatin by wrapping DNA around a nucleosome core comprised of histone proteins [1.Kouzarides T. Chromatin modifications and their function.Cell. 2007; 128: 693-705Abstract Full Text Full Text PDF PubMed Scopus (6568) Google Scholar]. Like beads on a string, the spacing of nucleosomes controls access to the genome and is regulated by adding or removing post-translational modifications to histone tails [1.Kouzarides T. Chromatin modifications and their function.Cell. 2007; 128: 693-705Abstract Full Text Full Text PDF PubMed Scopus (6568) Google Scholar]. Some modifications are associated with open chromatin and gene expression, like dimethylation of histone H3 at lysine 4 (H3K4me2), H3K36me3, and H3K79me [2.Li B. et al.The role of chromatin during transcription.Cell. 2007; 128: 707-719Abstract Full Text Full Text PDF PubMed Scopus (2261) Google Scholar]. Because they are commonly found at sites of active transcription, it is tempting to think that these modifications initiate transcription. However, these particular active histone modifications are only acquired during RNA polymerase (Pol) II elongation. We highlight here some of the evidence supporting H3K4me2 being cotranscriptionally acquired. However, similar evidence suggests that H3K36me3 and H3K79 methylation are also acquired cotranscriptionally [3.Xiao T. et al.Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast.Genes Dev. 2003; 17: 654-663Crossref PubMed Scopus (298) Google Scholar, 4.Steger D.J. et al.DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells.Mol. Cell. 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In Saccharomyces cerevisiae the H3K4 methyltransferase Set1/COMPASS (complex of proteins associated with Set1) associates with RNA Pol II to deposit H3K4 methylation at loci during transcription [9.Ng H.H. et al.Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity.Mol. Cell. 2003; 11: 709-719Abstract Full Text Full Text PDF PubMed Scopus (785) Google Scholar]. Evidence for the cotranscriptional (see Glossary) acquisition of H3K4me2 can be also be found in Drosophila S2 cells, where the pattern of genomic H3K4me2 is nearly identical to the occupancy of elongating RNA Pol II [10.Mito Y. et al.Genome-scale profiling of histone H3.3 replacement patterns.Nat. Genet. 2005; 37: 1090-1097Crossref PubMed Scopus (389) Google Scholar]. Furthermore, the cotranscriptional role of Set1 is conserved in other eukaryotes, where Set1 homologs associate with COMPASS-like complexes (called MLL complexes in mammals) [11.Shilatifard A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis.Annu. Rev. Biochem. 2012; 81: 65-95Crossref PubMed Scopus (460) Google Scholar]. If certain histone modifications are only acquired in the process of RNA Pol II elongation, why then bother adding active modifications at all? In the short term, coupling histone modification to transcription could ease the burden for future transcription. Active modifications help recruit ATP-dependent chromatin (or nucleosome) remodelers. In turn, these remodelers increase the spacing of nearby nucleosomes, which can then facilitate further RNA Pol II elongation [12.Clapier C.R. Cairns B.R. The biology of chromatin remodeling complexes.Annu. Rev. Biochem. 2009; 78: 273-304Crossref PubMed Scopus (1194) Google Scholar]. This self-reinforcing cycle may help maintain transcription at certain loci over time [13.Smolle M. Workman J.L. Transcription-associated histone modifications and cryptic transcription.Biochim. Biophys. Acta. 2013; 1829: 84-97Crossref PubMed Scopus (103) Google Scholar]. However, in the long term, coupling histone modification to transcription may also have an additional epigenetic function: maintaining gene expression patterns through cell division. Here, we describe the breadcrumb model, inspired by the German fairy tale 'Hansel and Gretel' (Figure 1, Key Figure) [14.Grimm J. Grimm W. Kinder- und Hausmärchen.7th edn. Vol. 2. Dieterich, 1857Google Scholar]. In the story, a woodcutter's family is so poor that it can barely feed itself. In desperation, the parents decide to abandon their children, Hansel and Gretel, in the forest to fend for themselves. On the first abandonment, the clever children use white pebbles to leave a trail back to their home; but when they are abandoned for a second time, Hansel and Gretel have only breadcrumbs to use for the trail. The birds of the forest soon peck away the breadcrumbs, leaving the children bereft in the woods. We suggest that active modifications are deposited cotranscriptionally, like a trail of breadcrumbs, to signify which loci have been expressed (Figure 1). To prevent aberrant gene expression, epigenetic reprograming factors may need to remove histone methylation at critical developmental time points in order to erase trails left by prior transcription. If histone methylation is maintained between cell divisions at a particular locus, it can establish an open chromatin state to facilitate transcription of this locus in each daughter cell. By preserving active chromatin through cell divisions, cells conserve energy by alleviating the need to reactivate genes from scratch. Evidence for this type of transcriptional maintenance can be seen in budding yeast, where patterns of transcriptional activation are maintained through cell division. This maintenance of transcription requires the COMPASS H3K4 methyltransferase complex, and is eliminated by mutating lysine 4 of histone H3 [15.Muramoto T. et al.Methylation of H3K4 is required for inheritance of active transcriptional states.Curr. Biol. 2010; 20: 397-406Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar]. Furthermore, in both yeast and human cells, the persistence of H3K4me2 enables certain loci that were previously transcribed to be more easily reactivated after multiple cell divisions, through their association with the nuclear pore [16.Light W.H. et al.A conserved role for human Nup98 in altering chromatin structure and promoting epigenetic transcriptional memory.PLoS Biol. 2013; 11e1001524Crossref PubMed Scopus (88) Google Scholar,17.D'Urso A. et al.Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory.Elife. 2016; 5e16691Crossref PubMed Scopus (40) Google Scholar]. However, it is important to note that although many histone modifications are associated with gene activation, only a subset function as transcriptional memory. For example, H3K4me2 is only acquired in gene bodies during RNA Pol II elongation. This is also likely the case for H3K36me3 and H3K79 methylation. In contrast, H3K4me1 is found at enhancers, and H3K4me3 is largely confined to promoters [8.Bannister A.J. Kouzarides T. Regulation of chromatin by histone modifications.Cell Res. 2011; 21: 381-395Crossref PubMed Scopus (2045) Google Scholar]. At these sites, the acquisition of H3K4me1 and H3K4me3 may be associated with RNA Pol II recruitment but likely does not require RNA Pol II elongation. These distinctions provide an opportunity for the genome to distinguish between loci that are functionally producing mRNAs versus those that are simply poised for future transcription. For example, in certain cases, H3K4me1 and H3K4me3 may function as a transcriptional memory, in a way that is similar to H3K4me2. Examples of H3K4me3 functioning as transcriptional memory include bivalent chromatin during embryonic stem cell (ESC) differentiation (see later), or at loci where H3K4me3 spreads over broad domains [18.Benayoun B.A. et al.H3K4me3 breadth is linked to cell identity and transcriptional consistency.Cell. 2014; 158: 673-688Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar]. In the case of these broad domains, it is possible that H3K4me3 is deposited along with RNA Pol II elongation. However, when H3K4me1 and H3K4me3 are deposited independently of RNA Pol II elongation, they may be associated with the maintenance of transcription over time, or just a consequence of transcription. Thus, the context may determine whether a particular modification functions as transcriptional memory. In support of the latter theory, H3K4me1 has recently been shown not to be required for transcription in ESCs [19.Dorighi K.M. et al.Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation.Mol. Cell. 2017; 66: 568-576Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. However, this finding does not preclude a potential role during differentiation, or the possibility that the function of H3K4me1 in vivo may differ from its role in cultured ESCs. The breadcrumbs of transcriptional memory also provide another, perhaps more important, advantage. Cell fates are often initiated by a precise combination of specific transcription factors acting together. Coupling histone methylation to transcription encodes a genome-wide transcriptional maintenance program with just a handful of histone modifications. Therefore, transcriptional memory allows a specific fate to be coordinately maintained in cells descended from the same progenitors, even in the absence of the original initiating transcription factors. Over time, through cell divisions, or even across generations, additional transcription can then further reinforce the pattern of gene regulation. Evidence for the role of transcriptional memory in maintaining cell fate can be found in Xenopus cloning experiments performed by Ng and Gurdon [20.Ng R.K. Gurdon J.B. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription.Nat. Cell Biol. 2008; 10: 102-109Crossref PubMed Scopus (222) Google Scholar]. Embryos derived from cloning via somatic cell nuclear transfer (SCNT) often inappropriately express genes from the original tissue that provided the somatic nucleus. This transcriptional memory of cell fate could not be maintained when lysine 4 of histone H3 was mutated, suggesting that the memory may be contained in the methylation of that residue [20.Ng R.K. Gurdon J.B. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription.Nat. Cell Biol. 2008; 10: 102-109Crossref PubMed Scopus (222) Google Scholar]. In addition, they showed that inappropriately retained H3K4 methylation inhibited the efficiency of cloning via SCNT [21.Hormanseder E. et al.H3K4 methylation-dependent memory of somatic cell identity inhibits reprogramming and development of nuclear transfer embryos.Cell Stem Cell. 2017; 21: 135-143Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. An elegant example of how the breadcrumb model contributes to cell fate can also be found early in Drosophila melanogaster embryonic development. Within a few dozen nuclear division cycles, the identity of future body segments is established through the sequential activation of segmentation genes, which encode different classes of transcription factors. Gap gene proteins are expressed first, which then activate pair-rule genes, which in turn activate segment polarity genes [22.St Johnston D. Nusslein-Volhard C. The origin of pattern and polarity in the Drosophila embryo.Cell. 1992; 68: 201-219Abstract Full Text PDF PubMed Scopus (998) Google Scholar]. Segment identity is determined by the combination of specific gap and pair-rule transcription factors present in the segment's progenitor cells. In Drosophila, the COMPASS-like H3K4 methylation complex is known as the Trithorax group (trxG) complex [23.Schuettengruber B. et al.Genome regulation by Polycomb and Trithorax: 70 years and counting.Cell. 2017; 171: 34-57Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. As segmentation genes are being expressed, Trithorax adds active H3K4me to reinforce an open chromatin state. After segmentation, when the original transcription factors are no longer present, an open chromatin state helps to maintain segment identity. Without Trithorax, the absence of H3K4me transcriptional memory causes the loss of segment identity. This loss of cellular fate manifests as a dramatic homeotic transformation of segments later in development [24.Kassis J.A. et al.Polycomb and Trithorax group genes in Drosophila.Genetics. 2017; 206: 1699-1725Crossref PubMed Scopus (29) Google Scholar]. Trithorax's activity is opposed by the Polycomb group (PcG) methyltransferase complex, which adds repressive H3K27me3 at silenced genes [24.Kassis J.A. et al.Polycomb and Trithorax group genes in Drosophila.Genetics. 2017; 206: 1699-1725Crossref PubMed Scopus (29) Google Scholar]. At any one specific locus, H3K4me tends to exclude H3K27me3, and vice versa. However, both modifications do coexist at some enhancers and promoters of important developmental genes. These regions of chromatin, called bivalent loci, help keep genes in stasis: H3K27me3 maintains an inactive state that persists throughout cell divisions, but the presence of H3K4me allows for rapid expression once the H3K27me3 is removed [25.Rada-Iglesias A. et al.A unique chromatin signature uncovers early developmental enhancers in humans.Nature. 2011; 470: 279-283Crossref PubMed Scopus (1164) Google Scholar,26.Bernstein B.E. et al.A bivalent chromatin structure marks key developmental genes in embryonic stem cells.Cell. 2006; 125: 315-326Abstract Full Text Full Text PDF PubMed Scopus (3422) Google Scholar]. Thus, the presence of repressive H3K27me3 enables the breadcrumbs of transcriptional memory to be maintained without requiring further transcription. This additional layer of regulation is particularly important in stem and progenitor cell populations, which are poised to rapidly choose between renewal versus differentiation into multiple lineages [27.Meissner A. Epigenetic modifications in pluripotent and differentiated cells.Nat. Biotechnol. 2010; 28: 1079-1088Crossref PubMed Scopus (266) Google Scholar]. Although transcriptional memory helps coordinate cell fates during development, it also presents a significant problem during fate transitions (Figure 1). For example, during fertilization, differentiated gametes need to completely reset their genomes to create a totipotent embryo. Stem cells face a similar problem in reverse, since they must swap multipotency for commitment to a specific lineage. Finally, even cells that have already attained terminal differentiation may face the continuous pressure of blocking an inappropriate reacquisition of multipotency. This review focuses on the role of histone methylation during cell fate transitions and how its misregulation in mammals compromises cell fates. We demonstrate how, in each of these three examples, the failure to sweep away the breadcrumbs can leave a false trail of transcription that ultimately contributes to disease. Sexual reproduction occurs when two gametes fuse to form a single-celled embryo. But because gametes are the product of a specialized developmental program, their genome bears a distinct transcriptional memory that is incompatible with embryonic development. The embryo is therefore faced with the task of repressing gametic factors while at the same time priming its genome for transcriptional plasticity. To accomplish both goals, the zygotic genome undergoes an extensive reprograming event shortly after fertilization. Reprogramming is accomplished primarily by maternal factors deposited in the oocyte, including histone modifiers. At recently expressed genes, they remove active modifications to prevent the re-expression of gametic genes, or deposit repressive modifications to ensure that these genes stay off (Figure 1C) [28.Wasson J.A. et al.Restoring totipotency through epigenetic reprogramming.Brief Funct. Genomics. 2012; 12: 118-128Crossref PubMed Scopus (4) Google Scholar]. For example, in the nematode Caenorhabditis elegans, the histone lysine demethylase SPR-5 plays an important role in epigenetic reprogramming. SPR-5 is a homolog of mammalian LSD1 (also called KDM1A or AOF2) that removes active H3K4me1/2 from genes previously expressed in the germline, including spermatogenesis genes [29.Katz D.J. et al.A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory.Cell. 2009; 137: 308-320Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar]. When SPR-5 is missing, H3K4me2 is inappropriately retained. After one generation without SPR-5, mutants experience only a slight increase of H3K4me2 in the genome, which has little effect on transcription. However, these higher levels of H3K4me2 are heritable between generations. In the continued absence of SPR-5, more H3K4me2 accumulates with each generation, until eventually enough is amassed to cause misregulation of gametic gene expression. Over a period of twenty generations, this gradual misregulation of gene expression causes spr-5 mutants to become progressively more sterile [29.Katz D.J. et al.A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory.Cell. 2009; 137: 308-320Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar]. In a similar manner, worms lacking the H3K9 lysine methyltransferase MET-2 (a homolog of mammalian SETDB1, which is also called KMT1E or ESET) gradually become sterile over twenty generations [30.Andersen E.C. Horvitz H.R. Two C. elegans histone methyltransferases repress lin-3 EGF transcription to inhibit vulval development.Development. 2007; 134: 2991-2999Crossref PubMed Scopus (88) Google Scholar]. Sterility is caused by the loss of repressive H3K9me2, which indirectly leads to the gradual accumulation of H3K4me2 [31.Kerr S.C. et al.SPR-5 and MET-2 function cooperatively to reestablish an epigenetic ground state during passage through the germ line.Proc. Natl. Acad. Sci. U. S. A. 2014; 111: 9509-9514Crossref PubMed Google Scholar]. In a single generation, neither spr-5 nor met-2 single mutants experience significant development defects, which is a testament to the resilience of epigenetic reprogramming. However, animals that lack both SPR-5 and MET-2 experience a substantial postembryonic developmental delay and become sterile within a single generation [31.Kerr S.C. et al.SPR-5 and MET-2 function cooperatively to reestablish an epigenetic ground state during passage through the germ line.Proc. Natl. Acad. Sci. U. S. A. 2014; 111: 9509-9514Crossref PubMed Google Scholar]. These striking phenotypes indicate that, even though reprogramming can handle either the loss of repressive H3K9me2 or the accumulation of active H3K4me2, it cannot tolerate the loss of two complementary factors. Development in C. elegans has the unusual feature of being invariant between individuals, which might allow it to proceed despite reprogramming errors. Conversely, in mammals, the loss of maternal reprogramming factors has much more serious consequences, as summarized in Table 1. Oocytes lacking the SPR-5 homolog LSD1 produce zygotes that fail to activate their zygotic genome and consequently die by the two-cell stage [32.Wasson J.A. et al.Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally.Elife. 2016; 5e08848Crossref PubMed Google Scholar,33.Ancelin K. et al.Maternal LSD1/KDM1A is an essential regulator of chromatin and transcription landscapes during zygotic genome activation.Elife. 2016; 5e08851Crossref PubMed Google Scholar]. Similarly, oocytes lacking the MET-2 homolog SETDB1 produce zygotes that develop slowly and die by the blastocyst stage [34.Kim J. et al.Maternal Setdb1 is required for meiotic progression and preimplantation development in mouse.PLoS Genet. 2016; 12e1005970Crossref PubMed Scopus (14) Google Scholar,35.Eymery A. et al.The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos.Development. 2016; 143: 2767-2779Crossref PubMed Scopus (14) Google Scholar]. Thus, mammalian embryogenesis appears to be more sensitive to the inappropriate retention of transcriptional memory. Intriguingly, partial loss of LSD1 in mouse oocytes gives rise to an occasional surviving pup that, upon adulthood, exhibits obsessive behavioral defects [32.Wasson J.A. et al.Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally.Elife. 2016; 5e08848Crossref PubMed Google Scholar]. The presence of adult phenotypes indicates that the failure to reprogram a single-cell embryo has consequences that can persist throughout many cell divisions and fate changes.Table 1The Maternal Effect of Chromatin Modifier Mutations in MiceName (complex)Alternative namesActivityM–Z+ molecular effectM–Z+ progeny effectRefsSetd1bHMT H3K4me2/3No change in H3K4me; transcriptional upregulation caused by aberrant repression of transcription factorsPolyspermy; arrest at one to two-cell stageBrici et al. (2017) [63.Brici D. et al.Setd1b, encoding a histone 3 lysine 4 methyltransferase, is a maternal effect gene required for the oogenic gene expression program.Development. 2017; 144: 2606-2617Crossref PubMed Scopus (20) Google Scholar]Kmt2dMll2, Mll4HMT H3K4me2/3Reduced H3K4me2/3; transcriptional misregulationArrest at one to two-cell stageAndreu‐Vieyra et al. (2010) [37.Andreu-Vieyra C.V. et al.MLL2 is required in oocytes for bulk histone 3 lysine 4 trimethylation and transcriptional silencing.PLoS Biol. 2010; 8e1000453Crossref PubMed Scopus (124) Google Scholar]Setd2HMT H3K36me3Decreased H3K36me2; spread of H3K4me3 and H3K27me3; aberrant H3K4me3 at imprinting control regions; loss of DNA methylationArrest at one-cell stageXu et al. (2019) [36.Xu Q. et al.SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development.Nat. Genet. 2019; 51: 844-856Crossref PubMed Scopus (4) Google Scholar]G9aEhmt2, Kmt1cHMT H3K9me1/2Loss of H3K9me2; transcriptional upregulation at four-cell stageDevelopmental delay; some arrest of preimplantation embryosZylicz et al. (2018) [64.Zylicz J.J. et al.G9a regulates temporal preimplantation developmental program and lineage segregation in blastocyst.Elife. 2018; 7e33361Crossref PubMed Scopus (6) Google Scholar] and Au Yeung et al. 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(2012) [69.Posfai E. et al.Polycomb function during oogenesis is required for mouse embryonic development.Genes Dev. 2012; 26: 920-932Crossref PubMed Google Scholar]Rnf2(PRC1)Ring1bHMT H3K27me3Single mutants had no effect; Ring1; Rnf2 double mutants have transcriptional misregulationRing1; Rnf2 double mutants arrest at two-cell stagePosfai et al. (2012) [69.Posfai E. et al.Polycomb function during oogenesis is required for mouse embryonic development.Genes Dev. 2012; 26: 920-932Crossref PubMed Google Scholar] and Terranova et al. (2008) [70.Terranova R. et al.Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos.Dev. Cell. 2008; 15: 668-679Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar]Kdm1aLsd1, Aof2KDM H3K4me1/2Accumulation of H3K4me and H3K9me; loss of DNA methylation at CpG islands; failed zygotic genome activationArrest at one to two-cell stage; rare survivors have behavioral abnormalitiesWasson et al. (2016) [32.Wasson J.A. et al.Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally.Elife. 2016; 5e08848Crossref PubMed Google Scholar], Ancelin et al. (2016) [33.Ancelin K. et al.Maternal LSD1/KDM1A is an essential regulator of chromatin and transcription landscapes during zygotic genome activation.Elife. 2016; 5e08851Crossref PubMed Google Scholar], and Stewart et al. 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