Epigenetics across the human lifespan

Abstract

Epigenetics has the potential to explain various biological phenomena that have heretofore defied complete explication. This review describes the various types of endogenous human developmental milestones such as birth, puberty, and menopause, as well as the diverse exogenous environmental factors that influence human health, in a chronological epigenetic context. We describe the entire course of human life from periconception to death and chronologically note all of the potential internal timepoints and external factors that influence the human epigenome. Ultimately, the environment presents these various factors to the individual that influence the epigenome, and the unique epigenetic and genetic profile of each individual also modulates the specific response to these factors. During the course of human life, we are exposed to an environment that abounds with a potent and dynamic milieu capable of triggering chemical changes that activate or silence genes. There is constant interaction between the external and internal environments that is required for normal development and health maintenance as well as for influencing disease load and resistance. For example, exposure to pharmaceutical and toxic chemicals, diet, stress, exercise, and other environmental factors are capable of eliciting positive or negative epigenetic modifications with lasting effects on development, metabolism and health. These can impact the body so profoundly as to permanently alter the epigenetic profile of an individual. We also present a comprehensive new hypothesis of how these diverse environmental factors cause both direct and indirect epigenetic changes and how this knowledge can ultimately be used to improve personalized medicine.

Keywords: development; diet; disease; environment; epigenetics; human lifespan.

Figure 1

A compilation of epigenetic influences on humans. The figure represents a compilation of the various epigenetic influences on humans by different sources present in the environment. While some of these might be beneficial for health and behavior, others might be harmful and interfere with the body and mind creating an imbalance, which might manifest as a disease or psychological disorder. Some of the beneficial influences listed are exercise, microbiome (beneficial intestinal bacteria), and alternative medicine whereas harmful influences include exposure to toxic chemicals and drugs of abuse. Factors such as diet, seasonal changes, financial status, psychological state, social interactions, therapeutic drugs, and disease exposure might have beneficial or harmful effects depending on the specific nature of the influence. The environment thus complements and shapes human health. With the help of extended research in the field, we might be able to steer these influences in a positive way.

Figure 2

Epigenetic regulation of OCT4 in stem cells, cancer cells and somatic cells. The figure represents the various epigenetic mechanisms involved in regulating the gene expression of OCT4. (A) This section represents the structure of the OCT4 gene. The green bar represents the coding region. The beige bar represents the upstream region containing regulatory sequences. The four pink bars represent conserved regions; CR1 (−129 to −1), CR2 (−1510 to −1315), CR3 (−1956 to −1852), CR4 (−2557 to −2425) (data for human OCT4 gene). The green triangles represent the sites for binding of activators and the red squares represent the sites for binding of the repressors and these sites lie within the enhancers and promoter. +1 denotes transcription start site (TSS). (DE, Distal Enhancer −2057 to −1955; PE, Proximal Enhancer −1152 to −901; PP, Proximal Promoter −240 to +1) (This data is for the OCT4 gene from mouse ESCs since information for human OCT4 was insufficient). (B) This section represents the regulation of OCT4 in ESCs and iPSCs. OCT4 is highly expressed in these cells. Binding of transcriptional machinery induces OCT4 expression. This can be attributed to the hypomethylated promoter, enhancer region, which promotes binding of transcriptional activators and co-activators like Pcaf, LRH−1, SF−1, and Brg1 sub-unit of the SWI-SNF nucleosome-remodeling complex, which in turn facilitates the binding of RNA polymerase II. Activating histone marks like H3K4me and H3K9Ac are found on the histones surrounding the regulatory regions of the gene and they enhance the recruitment and binding of transcription factors thus inducing gene expression. (C) This section represents the regulation of the OCT4 gene in cancer cells, where similar to embryonic-like cells, it is highly expressed. In the case of hepatocellular carcinoma, an additional layer of epigenetic regulation is seen with the activity of the OCT4-pseudogene (pg)4, a non-coding RNA that protects the OCT4 transcript from inhibition by miRNA-145. Thus, OCT4-pg4 indirectly enhances the expression of OCT4 in cancer cells by acting as a protective shell for nascent OCT4 transcripts. The activity of the Brg1 sub-unit of the SWI-SNF complex is not necessary for OCT4 expression in cancer cells. (D) This section represents the regulation of OCT4 in somatic cells, which are differentiated and have a specialized function. Here OCT4 expression is repressed because of the hypermethylated promoter region and the repressive H3K27me and H3K9me marks. This results in compaction of the regulatory regions and facilitates the recruitment of other transcriptional repressors like RAR, GCNF, COUP-TFs, further compacting the regulatory regions, and making it inaccessible to the transcriptional machinery. SNF5, a core sub-unit of the BAF complex (SWI-SNF) acts as a switch between pluripotency and differentiation and promotes differentiation by binding to regulatory regions of OCT4. In addition, the sumyolation of orphan nuclear receptor Tr2 at Lys 238 results in its release from promyelocytic (PML) nuclear bodies. (In ESCs and iPSCs Tr2 is bound to PML nuclear bodies and acts as an activator). This in turn results in an exchange of co-repressor Rip-140 for co-activator Pcaf, making Tr2 a repressor. Also, miR-290 through miR-295 enhance methylation as they inhibit Rb12, which would otherwise inhibit the activity of de novo methyl transferase Dnmt 3a/3b.

Figure 3

The direct and indirect epigenetic pathway. The figure represents two different routes through which an epigenetic factor can modify the epigenome leading to altered gene expression. Epigenetic effects exerted by an external factor or intrinsic environment can lead to direct and indirect effects on the epigenome. Green represents direct effects of an epigenetic factor and red represents indirect effects of an epigenetic factor. The direct pathway can operate in two different ways; namely Type1 and Type 2. In the Type 1 direct pathway, the epigenetic factor directly exerts an effect on the epigenetic enzymes such as DNMTs, HDACs, HATs, HMTs, HDMs, etc. such that there is an altered bioavailability of these enzymes in the cell. A Type 2 direct effect is when an epigenetic factor interferes with a biochemical pathway such that there is altered availability of a metabolite required for constituting an epigenetic tag. Both cases can result in aberrant or inadequate recruitment of epigenetic tags in a random fashion to non-specific promoters, ultimately establishing an altered epigenetic profile. In the indirect pathway, the epigenetic factor indirectly exerts an effect on the epigenome by first interfering with any signaling pathways of the cell. An acute exposure to the epigenetic factor can cause altered expression of growth factors, receptors, ion channels and so on resulting in non-homeostatic cellular processes. This in turn might lead to an altered status of transcriptional machinery (bound or unbound to the promoter/enhancer) and its bioavailability in a cell. A chronic exposure to the epigenetic factor might lead to retention of such state of transcriptional machinery (bound or unbound to the promoter/enhancer) causing altered gene expression as well as aberrant recruitment of epigenetic enzymes, leading to permanent addition or removal of epigenetic tags to specific promoter/enhancers. This consequently establishes an altered epigenetic profile.

Figure 4

The indirect epigenetic pathway. An epigenetic factor operating through an indirect pathway interferes with transcriptional machinery. Chronic exposure to an epigenetic factor can lead to the retention of an already altered state of transcriptional machinery. The transcriptional machinery (bound or unbound to the gene regulatory regions i.e., promoters/enhancers) includes a number of proteins like transcription factors, activators and co-activators, repressors and co-repressors and nucleosome or chromatin remodeling complexes. For simplicity, these proteins are Fectively termed as “Gene regulatory protein” for this figure. (A) A gene regulatory protein might affect the status of RNA Polymerase (1) By inhibiting it from binding to a transcriptional apparatus or forming one or (2) by facilitating the binding of RNA Polymerase as well as formation of a transcriptional apparatus essential for the initiation of transcription. (B) A gene regulatory protein might also affect the status of epigenetic enzymes like DNMTs, HDACs, HATs, HMTs, HDMs, etc., which are responsible for the addition or removal of epigenetic tags (methyl group on DNA or histone, acetyl group on histones) on gene regulatory regions. This can be (1) By inhibiting epigenetic enzymes from binding to the gene regulatory regions and hence prohibiting the addition or removal of epigenetic tags (2) By facilitating the binding of epigenetic enzymes to gene regulatory regions and hence allowing the addition or removal of epigenetic tags. Such retention of a gene regulatory protein due to chronic exposure to an epigenetic factor might result in a permanent change in the epigenetic profile and/or gene expression of a specific gene affected by that epigenetic factor through an indirect pathway.

Figure 5

Chronology of epigenetic regulation during the circadian rhythm and menstrual cycle. The regulation of biological cycles like the Circadian rhythm and Menstrual cycle in females has been shown to work through epigenetic regulatory mechanisms. (The figure is relative and not accurate to scale). (A) The gene Bmal1 is the master regulator of the circadian rhythm. The graph represents the relative density of the two active histone marks H3K3me and H3K4me on Bmal1 through a 26-hour period. ZT is Zeitgeber Time where ZT0 corresponds to light on and ZT12 to light off. The peaks represent the maxima of the two-histone marks with respect to ZT, similarly, the dips represent the minima. This shows differential expression of the gene with respect to time, which has an epigenetic regulatory basis. (B) The graph represents the global acetylation profile from endometrial tissue through the 28-day menstrual cycle. The peaks represent the maxima and the dips represent the minima of the histone marks with respect to time. Global changes in the histone acetylation profile show that these marks contribute to the induction of different genes during different stages of the cycle. Hence they are responsible for the variable morphology of the endometrium through the 28-day period. These epigenetic changes are thus the basis for changes in the endometrial morphology like regeneration (1–7 days), proliferation (7–14 days), ovulation (13–17 days), differentiation (15–22 days), degradation (22–28 days) during the proliferative phase and secretory phase.

Figure 6

Chronology of epigenetics during the life of a human female. This figure is a summary of the most important events in the lifetime of a human female, which contribute toward her physical and mental development, and the genes responsible for such changes are listed. (We chose a female because the lifetime of a female has more descriptive events compared to a male). The life of a female can be divided into four stages: (A) Development (0–9 months), (B) Childhood (0–7 years) and Adolescence (7–17 years), (C) Adulthood (18–50 years) and Menopause (50–65 years), (D) Old Age and Death (65–90 years). Genes in green represent those, which are expressed/induced, and the ones in red represent the genes repressed/silenced during a particular stage of life, and contributing to a specific phenotype. The symbol denotes hypermethylation and denotes hypomethylation, usually of the promoter of the gene. For example, puberty is initiated when genes like KISS-1 (shown in green) is induced. Aging is associated with silencing or down-regulation of SIRT1 gene (represented in red). [PCG, primordial germ cells; FGF21, Fibroblast growth factor 21; ARC, Age-related cataract; CRYAA, chaperone-like activity of αA-crystalline; AMD, Age-related macular degeneration; GSTM, Glutathione S-transferase isoform mu1 (GSTM1) and mu5 (GSTM5)].