Role of Epigenetics in Developmental Biology and Transgenerational Inheritance Birth Defects Research
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Birth Defects Research (Part C) 93:51–55 (2011) REVIEW Role of Epigenetics in Developmental Biology and Transgenerational Inheritance Michael K. Skinner* The molecular mechanisms involved in developmental biology and cellu- opment of a cell or tissue. These lar differentiation have traditionally been considered to be primarily environmental factors include genetic. Environmental factors that influence early life critical windows nutrition, environmental com- of development generally do not have the capacity to modify genome pounds, and stress. These factors sequence, nor promote permanent genetic modifications. Epigenetics generally do not have the ability provides a molecular mechanism for environment to influence develop- to directly promote DNA sequence ment, program cellular differentiation, and alter the genetic regulation of development. The current review discusses how epigenetics can mutations nor permanently alter cooperate with genetics to regulate development and allow for greater genetic processes. This fetal basis plasticity in response to environmental influences. This impacts area of adult onset disease clearly such as cellular differentiation, tissue development, environmental involves an abnormal develop- induced disease etiology, epigenetic transgenerational inheritance, and mental process, but is difficult to the general systems biology of organisms and evolution. Birth Defects explain on the basis of genetic Research (Part C) 93:51–55, 2011. VC 2011 Wiley-Liss, Inc. processes alone. Environmental factors can also promote altera- Key words: epigenetics; development; environment; transgenera- tions in normal development to tional; systems biology; differentiation; disease etiology induce developmental mutations and defects, but again most fac- tors have not been shown to alter CURRENT PARADIGM FOR be regulated primarily from DNA sequence. On a population THE MOLECULAR CONTROL genetic mutations. The role of level, many evolutionary proc- OF DEVELOPMENTAL genetics in the regulation of devel- esses appear to be influenced by environmental factors to promote BIOLOGY opmental biology is well estab- lished and many studies support rapid alterations in development Traditionally genetic mechanisms the actions of numerous genes and adaptations, which are also and processes have been thought and genetic processes. As with difficult to explain with genetic to provide the primary control for any area of biology, genetics is a mechanisms alone. cellular differentiation and devel- critical element of the normal and An additional molecular mecha- opmental biology. This involves abnormal development of a cell, nism that can complement genet- the regulation of genome activity tissue or organism. However, ics to influence developmental through a series of genetic factors there are several observations biology is epigenetics. The ability such as a cascade of critical tran- that suggest genetics alone is not of environment to influence devel- scription factors, regulation of sufficient to regulate the entire opment can also be facilitated by gene expression to promote a pro- phenomena of development or epigenetic processes. The para- gramming of transcriptional systems biology. digm that genetics is the primary events essential for cellular differ- Abnormal development and criti- factor to regulate developmental entiation and eventual develop- cal windows of exposure have biology is limited and ignores the ment of the tissue and organism. demonstrated environmental fac- plasticity to respond rapidly to Abnormal development associated tors can promote adult onset dis- environment, nor does it explain with events such as disease devel- ease, which is associated with abnormal development and dis- opment have also been thought to early alterations in normal devel- ease etiology in the absence of Michael K. Skinner is from the Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA *Correspondence to: Michael K. Skinner, Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236. E-mail: [email protected] View this article online at wileyonlinelibrary.com. DOI: 10.1002/bdrc.20199 VC 2011 Wiley-Liss, Inc. 52 SKINNER Figure 1. Epigenetic and genetic cascade of events involved in development. genetic alterations. Epigenetics was DNA methylation (Holliday genes (Turner, 1998). These his- provides an additional molecular and Pugh, 1975) in the 1970s tone modifications are not gener- mechanism to complement genet- which was subsequently shown to ally involved in establishing the ics in the regulation of develop- influence processes such as X absence or presence of expression ment. Therefore, the paradigm chromosome inactivation and of a specific gene, but the subse- shift is that layers of molecular gene expression (Chen and Riggs, quent expression and responsive- control and cascades of both epi- 2005). In the late 1980s imprinted ness to transcriptional control genetic and genetic factors or genes were identified and shown (Turner, 1998). The chromatin processes are involved in regulating to be regulated by DNA methyla- structure can modulate gene developmental biology, Figure 1. tion as well (Chen and Riggs, expression at a distance through This provides a more robust and 2005). In the 1990s histone modi- looping, nuclear matrix association thorough control of development fications and chromatin structure and nucleosome positioning that integrates these two critical were identified and shown to regu- (Biddie, 2011). The noncoding molecular processes. late promoter activity and gene sRNAs can act at a distance to expression (Turner, 1998). In regulate gene expression through 2000, small noncoding RNAs were promoter modulation and can Epigenetics found to have epigenetic activity influence other epigenetic factors Epigenetics is defined as molec- and regulate gene expression (Wan and Bartolomei, 2008). The ular factors and processes around (Berdasco and Esteller, 2010). combination of all these elements DNA that regulate genome activ- Around 2005 the first genome creates the epigenome and a com- ity, independent of DNA sequence, wide mapping of the epigenome plex regulation of genome-wide and that are mitotically or meioti- appeared (Pokholok et al., 2005). activity. All these factors are criti- cally stable (Skinner et al., 2010). Therefore, the molecular charac- cal and play distinct roles in the The term heritable has been terization of epigenetics is rela- process. In regards to develop- used, but is defined as genera- tively new and additional epige- ment, the DNA methylation tional inheritance by definition so netic marks are likely to be is thought to have the initial does not include all elements of identified in the future (e.g., programming role followed by epigenetics. Therefore, mitotically hydroxy-methylcytosine) (Kriau- chromatin structure and histone stable is more precise and clarifies cionis and Heintz, 2009). modifications to fine tune the reg- that as the cell undergoes mitosis The functions of the various epi- ulation of gene expression at the the epigenome is replicated. An genetic marks and factors are dis- various stages of differentiation environmentally induced stable tinct. The DNA methylation has a and development. alteration in the epigenome can role in early development to help An important aspect of epige- permanently alter the regulation establish early cell lineages (e.g., netics, first clarified by Arthur of genome activity during cell dif- stem cells) and can regulate the Riggs (Russo et al., 1996), is that ferentiation and development activity of promoters and general the epigenetic marks are mitoti- processes. genome regions (e.g., repeat ele- cally and meiotically stable. The The origin of the use of the term ments) (Kazazian, 2004). Many initial reference was to heritable, epigenetics was by Conrad Wad- DNA methylation events are distal but the term heritable is most dington in the 1940s while he was to promoters, but can influence commonly defined as generational studying environment—gene inter- gene expression (Illingworth and transmission (i.e., inheritance). actions to promote phenotypes Bird, 2009). Histone modifications Therefore, a more accurate term is (Van Speybroeck, 2002; Wadding- are primarily localized in the pro- ‘‘mitotically stable’’ and implies as ton, 1940, 1956). The first molec- moter and gene regions and fine a cell divides or proliferates the ular epigenetic factor identified tune the regulation of specific epigenetic marks constituting the Birth Defects Research (Part C) 93:51–55, (2011) ROLE OF EPIGENETICS 53 epigenome are replicated. If an function. This environmental epi- velopmental biology. They should epigenetic mark or change was genetics will have a critical impact not be viewed as conflicting or not mitotically stable, then the on the developmental process and opposing processes, but when mark would only be relevant in the functions of cells or tissues later in integrated provide a more robust individual cell and would not be life after the environmental expo- molecular control of developmen- important outside that cell’s func- sure is removed. Environmental tal biology. tion. When an epigenetic mark is factors can include nutritional fac- A cascade of genetic and tran- mitotically stable, then all cells tors, environmental compounds or scriptional events allows a cell or that come from that initial cell will stress (Jirtle and Skinner, 2007; tissue to develop