sign in sign up
<<
Home , Developmental biology, Embryology, Epigenetics

Birth Defects Research (Part C) 93:51–55 (2011) REVIEW

Role of in Developmental and Transgenerational Inheritance

Michael K. Skinner*

The molecular mechanisms involved in and cellu- opment of a or . These lar differentiation have traditionally been considered to be primarily environmental factors include genetic. Environmental factors that influence early critical windows , environmental com- of generally do not have the capacity to modify 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 , and alter the genetic regulation of development. The current review discusses how epigenetics can nor permanently alter cooperate with to regulate development and allow for greater genetic processes. This fetal basis plasticity in response to environmental influences. This impacts area of 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 of and . 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 and , 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 . 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 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 (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 inactivation and of a specific gene, but the subse- shift is that layers of molecular (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 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 modi- looping, nuclear matrix association thorough control of development fications and chromatin structure and positioning that integrates these two critical were identified and shown to regu- (Biddie, 2011). The noncoding molecular processes. late activity and gene sRNAs can act at a distance to expression (Turner, 1998). In regulate gene expression through 2000, small noncoding 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 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 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 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 . 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 from a have the same epigenome. There- Skinner et al., 2010). Any external or basal state to a more mature or fore, early in life an environmental factor that can modulate normal adult stage of development. This signal could modify a cell’s epige- development and the epigenome requires many steps and each netic marks that then would be can be considered an environmen- step needs to be carefully con- mitotically stable and appear later tal insult that impacts genome ac- trolled to allow the next step to in development in the tissue the tivity without altering DNA proceed, Figure 1. As there is cells reside. Therefore, the epige- sequence. The mitotic stability of a cascade of genetics steps, there nome is programmed and main- the epigenome suggests an envi- is also a cascade of epigenetic tained in a cell population as it ronmental insult, even after its re- steps to cooperate with genetics further differentiates and is associ- moval, will have a lasting effect on to promote the developmental ated with the development of any cell differentiation and develop- pathway. The epigenetic processes tissue or organism. As the epige- ment to promote alterations in can respond to environmental fac- nome regulates gene expression, later in life. This pro- tors to then integrate with the the environmental or developmen- vides a molecular mechanism for genetic processes to lead to a de- tal shifts in the epigenome can the fetal basis of adult onset dis- velopmental step. The cascade of become a critical element affecting ease or the developmental basis of epigenetic and genetic steps dur- the developmental process. The disease (Barker et al., 2009; ing development is critical to pro- process of mitotic stability for DNA Bruce and Hanson, 2010). In addi- mote the normal development methylation is understood, but tion, this provides a mechanism process, Figure 1. Early in devel- how histone modifications and for environmental not opment there are critical windows chromatin structure are replicated previously considered, and of development that are more re- and transmitted through cellular explains how an early life expo- sponsive to environmental factors division is not as well understood. sure can promote a later life phys- to modify development. Later in For example, during DNA replica- iological effect. Environmental epi- development, the adult or at a tion associated with mitosis, the genetics will be a critical concept more mature stage, the develop- parental DNA strand has a methyl- to consider in developmental biol- mental process has been pro- ated and as the new ogy, as well as most areas of biol- grammed and is less responsive to strand of DNA is synthesized ogy (Jirtle and Skinner, 2007; environmental factors to alter de- the associated methyltrasferase Skinner et al., 2010). velopment. In the event an early methylates the hemimethylated critical window was influenced DNA to replicate the original Integration of Epigenetics and through an alteration in the cas- parental strand epigenetic mark. cade of epigenetic events, the final Genetics in Developmental Further research is needed to stage of development can be elucidate how the complete epige- Biology modified from the normal develop- nome is replicated and mitotically Genetics has a central role in mental state, Figure 1. This is gen- stable. This aspect of epigenetics biology and in the control of de- erally reflected in the genome ac- is critical and allows for a dramatic velopment. Observations for the tivity or transcriptome of the dif- influence on development and past several decades have identi- ferentiated cells or tissue. The biology. fied many specific genes and result of this cascade of epigenetic As the epigenetic marks that genetic processes involved in the and genetic processes and the make up the epigenome are development of most cells, tis- final influence on cell and tissue mitotically stable, an alteration in sues and organisms. Epigenetics genome activity is the differentia- the epigenome early during cell is an additional molecular process tion and development of the cell, differentiation or development is that can influence development tissue and organism. Abnormal transmitted through that cells line- and provides a mechanism development and alterations in the age to later stages of development for the environment and early normal cascade of events through of the tissue or organism. There- life events to regulate cell differ- these mechanisms are likely to be fore, environmental factors that entiation and development. a significant element of disease can alter the epigenome promotes Therefore, epigenetics and genet- etiology. The overall process and an abnormal programming that ics compensate and cooperate integration of epigenetics and permanently alters the cell, tissue to control and regulate most genetics leading to these develop- or organism development and biological processes, including de- mental processes provides the

Birth Defects Research (Part C) 93:51–55, (2011) 54 SKINNER systems biology of the tissue or Guerrero-Bosagna C et al., 2010; ceptibility to develop disease organism, Figure 1. Skinner et al., 2010) to then (Skinner et al., 2010). As all de- transmit this altered germ line epi- velopment and differentiation genome to subsequent genera- processes involve a cascade of Epigenetic Transgenerational tions (Anway et al., 2005; Anway epigenetic and genetic steps, Inheritance et al., 2006a,b; Anway and Skin- alteration of the baseline epige- The inheritance of environmen- ner, 2008; Guerrero-Bosagna C nome, similar to alteration in the tally induced phenotypes is the or- et al., 2010; Skinner et al., 2010). genetic baseline, will have the igin of the concept of epigenetics As the embryonic stem cell epige- capacity to promote abnormal de- (Waddington, 1940; 1956). In the nome is altered due to this germ velopment which may lead to dis- event these environmental factors line transmission, all cell popula- ease later in life. For this reason, modify the epigenome of the germ tions and tissues will have an environmentally induced epige- line and this becomes permanently altered epigenome and corre- netic transgenerational inheritance programmed (imprinted) then the sponding transcriptome (Anway through the germ line will have a altered epigenome and et al., 2008; Skinner et al., 2010). significant impact on developmen- become transgenerational and The germ line generated by the tal biology. This mechanism and appear in subsequent progeny and next generation will also have this consideration of the cascade of generations in the absence of any altered epigenome and transmit it integrated epigenetic and genetic further environmental exposures to the subsequent generation events during development, (Anway et al., 2005; Daxinger and (Guerrero-Bosagna C et al., 2010; Figure 1, will be an important factor Whitelaw, 2010; Jirtle and Skin- Skinner et al., 2010). Exposure to in disease etiology not previously ner, 2007; Skinner et al., 2010). the endocrine disruptors at other considered (Skinner et al., 2010). The mechanism involves the times of development do not In addition to the effects of epi- actions of an environmental factor appear to have the capacity to genetic transgenerational inheri- at a critical time of gonadal permanently alter the germ line tance on developmental biology determination in the mammalian epigenome (Anway et al., 2005; and disease etiology, this phenom- when the germ line cell fate Anway and Skinner, 2008; Skinner ena will impact nearly all areas of is determined and the primordial et al., 2010). Of course, the vast biology, including evolutionary differentiates into a male majority of exposures will alter the biology (Crews et al., 2007). If the or female germ lineage (Skinner cells at critical periods of base-line epigenome is modified, et al., 2010). During this critical development to modify later cellu- similar to the base-line effects of period of development of the germ lar development and potential genetics, then the biological sys- line an erasure of DNA methyla- adult onset disease, Figure 1, but tem will respond by altering the tion occurs and then upon gonadal this does not have the capacity to phenotype, physiology, and gen- sex determination the germ line become transgenerational as the eral biology of the organism. In DNA is remethylated in a male or germ line is not involved (Skinner considering the molecular mecha- female specific manner (Durcova- et al., 2010). Epigenetic transge- nisms that promote an Hills et al., 2006). The actions of nerational inheritance through a event and to an environmental factor such as permanently altered epigenome of allow an evolutionary event, an an (Anway the germ line has the capacity to integration of epigenetics and et al., 2005; Anway et al., 2006b; have a dramatic influence on de- genetics will be equally as impor- Anway and Skinner, 2008) can velopmental biology, as well as tant. The current paradigm of DNA modify this germ line methylation other areas of biology such as mutational events promoting evo- and promote a permanently evolution. lution is accurate, but the inclusion altered epigenome (Anway et al., In the event the base-line epige- of epigenetics allows for a much 2005; Guerrero-Bosagna C et al., nome is altered, then the cascade higher degree of variability in the 2010) in the germ line (e.g., of epigenetic and genetic steps biological system to facilitate an ) that gets transmitted to during development will be altered adaptation event. In addition, the subsequent generations transge- and a modified differentiated or inclusion of epigenetics allows for nerationally (Anway et al., 2005; developmental state achieved, a mechanism to have environment Anway et al., 2006a,b; Anway and Figure 1. Therefore, epigenetic influence evolutionary processes. Skinner, 2008; Guerrero-Bosagna transgenerational inheritance has Therefore, epigenetic transgenera- C et al., 2010). Therefore, the ba- a dramatic effect on the develop- tional inheritance is a novel pro- sic mechanism of epigenetic trans- mental biology of all cells and tis- cess to consider in evolutionary generational inheritance involves sues derived from the germ line biology not previously considered. the actions of an environmental transmitting this modified base- This does not alter the basic Dar- factor (e.g., chemical or nutrition) line epigenome. Although not all winian evolutionary paradigm, but during germ line remethylation at cell types or tissues will develop a simply provides a neo-Lamarckian gonadal sex determination to per- disease state, those tissues that component and more diverse manently alter the germ line epi- have a sufficiently altered tran- molecular mechanism to be genome (Anway et al., 2005; scriptome will have a greater sus- involved. Future research into the

Birth Defects Research (Part C) 93:51–55, (2011) ROLE OF EPIGENETICS 55 integration of epigenetics and in the base-line epigenome in the preference. Proc Natl Acad Sci USA genetics will likely reveal more germ line through its integration 104:5942–5946. powerful mechanistic considera- with genetic processes and the Daxinger L, Whitelaw E. 2010. Trans- generational epigenetic inheritance: tions to be applied to all areas of cascade of events required in a more questions than answers. Ge- biology, including evolutionary developmental system, Figure 1, nome Res 20:1623–1628. biology (Skinner et al., 2010). will have the capacity to alter phe- Durcova-Hills G, Hajkova P, Sullivan S, notype (Waddington, 1940, 1956) Barton S, Surani MA, McLaren A. 2006. Influence of sex chromosome and biological processes such as constitution on the genomic imprint- evolution (Crews et al., 2007). ing of germ cells. Proc Natl Acad Sci CONCLUSIONS The complementary and inte- USA 103:11184–11188. Guerrero-Bosagna C, Settles M, Lucker Epigenetics will have a critical role grated roles of epigenetics and genetics is what allows these new BJ, Skinner MK. 2010. Epigenetic in developmental biology and dif- transgenerational actions of vinclozo- ferentiation due to its function in developmental events to occur lin on promoter regions of the sperm regulating genome activity and and create new phenotypes. epigenome. PLoS ONE 5:e13100. the mitotic stability of the epige- Holliday R, Pugh JE. 1975. DNA modifi- cation mechanisms and gene activity netic marks to be replicated as REFERENCES during development. Science cells proliferate. Therefore, epige- 187:226–232. netic marks and alterations in the Anway MD, Cupp AS, Uzumcu M, Skin- Illingworth RS, Bird AP. 2009. CpG ner MK. 2005. Epigenetic transge- epigenome have the capacity to islands—‘‘a rough guide.’’ FEBS Lett nerational actions of endocrine dis- 583:1713–1720. be maintained within a cell type or ruptors and male fertility. Science Jirtle RL, Skinner MK. 2007. Environ- population for the life span of the 308:1466–1469. mental and disease sus- organism. As an integration and Anway MD, Leathers C, Skinner MK. ceptibility. Nat Rev Genet 8:253– cascade of epigenetic and genetic 2006a. Endocrine disruptor vinclozo- 262. lin induced epigenetic transgenera- processes are required throughout Kazazian HH Jr. 2004. Mobile ele- tional adult-onset disease. Endocri- ments: drivers of genome evolution. development, Figure 1, modifica- nology 147:5515–5523. Science 303:1626–1632. tion of an epigenetic state has the Anway MD, Memon MA, Uzumcu M, Kriaucionis S, Heintz N. 2009. The capacity to create a new pheno- Skinner MK. 2006b. Transgenera- nuclear DNA base 5-hydroxymethyl- tional effect of the endocrine disrup- type, and if abnormal a disease is present in Purkinje tor vinclozolin on male spermatogen- and the brain. Science state. In contrast to genetics, epi- esis. J Androl 27:868–879. 324:929–930. genetics can be modified readily Anway MD, Rekow SS, Skinner MK. Pokholok DK, Harbison CT, Levine S, by environmental factors, such 2008. Transgenerational epigenetic Cole M, Hannett NM, Lee TI, Bell GW, that epigenetics provides a molec- programming of the embryonic testis Walker K, Rolfe PA, Herbolsheimer E, transcriptome. 91:30–40. ular mechanism for the environ- Zeitlinger J, Lewitter F, Gifford DK, Anway MD, Skinner MK. 2008. Trans- Young RA. 2005. Genome-wide map ment to alter genome activity and generational effects of the endocrine of nucleosome and meth- developmental biology. Future disruptor vinclozolin on the ylation in . Cell 122:517–527. considerations of the molecular transcriptome and adult onset dis- Russo VEA, Martienssen RA, Riggs AD. ease. Prostate 68:517–529. processes involved in developmen- 1996. Epigenetic mechanisms of Barker DJ, Osmond C, Kajantie E, gene regulation. Woodbury: Cold tal biology, as well as other areas Eriksson JG. 2009. Growth and Spring Harbor Laboratory Press. of biology, requires a considera- chronic disease: findings in the Hel- Skinner MK, Manikkam M, Guerrero- tion of epigenetic processes. sinki Birth Cohort. Ann Hum Biol Bosagna C. 2010. Epigenetic trans- The germ line creates through 36:445–458. generational actions of environmen- Berdasco M, Esteller M. 2010. Aberrant developmental biology nearly all tal factors in disease etiology. Trends epigenetic landscape in : how Endocrinol Metab 21:214–222. species. Genetic modifications in cellular identity goes awry. Dev Cell Turner BM. 1998. Histone acetylation DNA sequence have the capacity 19:698–711. as an epigenetic determinant of long- to dramatically alter the develop- Biddie SC. 2011. Chromatin architec- term transcriptional competence. Cell ture and the regulation of nuclear re- ment of a species. As epigenetics Mol Life Sci 54:21–31. ceptor inducible . J Neu- Van Speybroeck L. 2002. From epigen- is intimately integrated with roendocrinol 23:94–106. esis to epigenetics: the case of C. H. genetics, alterations in the germ Bruce KD, Hanson MA. 2010. The de- Waddington. Ann NY Acad Sci line epigenome also has the velopmental origins, mechanisms, 981:61–81. capacity to dramatically alter the and implications of metabolic syn- Waddington CH. 1940. Organisers and drome. J Nutr 140:648–652. development of a species. There- genes. Cambridge: Cambridge Uni- Chen ZX, Riggs AD. 2005. Maintenance versity Press. fore, epigenetic transgenerational and regulation of DNA methylation Waddington CH. 1956. Principles of inheritance induced by environ- patterns in . Biochem Cell . London: George Allen & mental factors will have a critical Biol 83:438–448. Unwin Ltd. Crews D, Gore AC, Hsu TS, Dangleben role in the biology, disease etiol- Wan LB, Bartolomei MS. 2008. Regula- NL, Spinetta M, Schallert T, Anway tion of imprinting in clusters: noncod- ogy and general development of MD, Skinner MK. 2007. Transgenera- ing RNAs versus insulators. Adv Genet most, if not all, species. A change tional epigenetic imprints on mate 61:207–223.

Birth Defects Research (Part C) 93:51–55, (2011)