“Omics” as the filtering gateway between environment and phenotype: The inflammatory bowel diseases example

To the Editor:The developmental origins hypothesis postulates that environ-mental inﬂuences during critical periods of development caninduce permanent changes in organismic structure and functionthat can alter adult metabolism and disease risk [Waterland andMichels, 2007; Gluckman et al., 2010]. As the advancing high-throughput technologies have brought us into the ‘‘omics’’ eraof molecular biology, we can distinguish large, dynamically inter-acting families of molecules and molecular processes, into which,the chronological and spatial memory of a lifetime is intimatelyhidden (Fig. 1). It is this complex network of molecular memorywhere, at critical periods of development, vibrant forces oforganismic environment may leave a permanent mark.The building blocks of ‘‘omics’’ are frequently hierarchicallycategorized based on our current knowledge and concepts inbiology [Barnettet al.,2010].Approaching thishierarchy,onecanstate that from metabolomics to genomics there is an increasedstability and heritability, while a reversely enhanced ﬂexibility andcomplexity characterizes these large molecular and functionalcategories (Fig. 1). For instance, the fundamental nature of geno-mics is transgenerational (meiotic) inheritance. For speciﬁc non-imprinted epigenomic changes in mammals; however, there is atbest only weak evidence for true transgenerational inheritance[Waterland et al., 2007; Jablonka and Raz, 2009], which is likelyduetomassiveepigenomicerasureingermcellsandembryos[Poppet al., 2010]. Meanwhile, the potential for mitotic inheritance iswithin the deﬁnition of epigenetic processes, but less is knownabout the mitotic inheritance of proteins and their post-divisionstability [Fuentealba et al., 2008].Secondary to increased ﬂexibility and responsiveness, environ-mentalexposurescaneasilyinﬂuencemetabolomics;whereaslowerin the cascade, genomics is relatively well protected from extracel-lular/extracorporeal stimuli. In the meantime, it is the moreprominently inherited omic groups that can potentially inducepermanent phenotypic alterations. Therefore, one can envision‘‘omics’’astheﬁlteringgatewaybetweenenvironmentandpheno-type (Fig. 2A), which on one hand provides protection fromnoxious insults, and on the other hand inherently supports thecapability for long-term adaptation. In reality; however, environ-mental effects are more likely to modulate phenotypic outcomesthrough the hierarchically interacting omic cascade, rather thandirectly at each level. The initiation of metabolomic changes caneventually reach the epigenome and possibly even the genome.Naturally, it is by this same intricate omic network that genomicchangesultimatelyleadtophenotypemodiﬁcationsinareverseandfrequentlyunpredictablefashion[Kellermayer,2007;FeinbergandIrizarry, 2010] (Fig. 2B). The murine metastable epialleles arestriking examples for this environment-through-epigenome-to-phenotype cascade. At these loci, DNA methylation (the methyla-tion of cytosines in CpG dinucleotides, the most stable epigeneticmark),feedingoffthemammalianonecarbonpool,canbeshiftedat the population level leading to permanent phenotype changessecondary to modiﬁed prenatal environments [Dolinoy et al.,2007]. Importantly, DNA methylation is potentially mutagenicthrough spontaneous and active deamination [Morgan et al.,2004;Caoetal.,2009],andcanexertgenomiceffectsbypersistentlysuppressing the translocation of transposable elements [Bestor,2000], thereby providing the ﬁnal step from metabolomics togenomics in the ‘‘omics’’ cascade.