Environmental Epigenetic Transgenerational Inheritance and Somatic Epigenetic Mitotic Stability

Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability

Michael K. Skinner Center for Reproductive Biology; School of Biological Sciences; Washington State University; Pullman, WA USA

he majority of environmental fac- is responsive to environmental factors and Ttors can not modify DNA sequence, can directly impact the genetic cascade of but can influence the epigenome. The events. Just as there is a cascade of genetic mitotic stability of the epigenome and steps during development, a cascade of ability of environmental epigenetics to epigenetic steps also exists and impacts influence phenotypic variation and dis- the transcriptional stages of cellular dif- ease, suggests environmental epigenetics ferentiation and development (Fig. 1). will have a critical role in disease etiology Environmental epigenetics provides a and biological areas such as evolutionary direct molecular mechanism for environ- biology. The current review presents the mental factors or toxicants to influence molecular basis of how environment can the genetic cascade of events involved in promote stable epigenomes and modified development, such that the environment phenotypes, and distinguishes the dif- can directly impact biology. An interest- ference between epigenetic transgenera- ing element of these integrated molecular tional inheritance through the germ line events for developmental biology1 is the versus somatic cell mitotic stability. fact that critical windows of susceptibility exist2 where the environmental factors Role of Environmental have a more dramatic ability to modify and Epigenetics in Development impact important stages of development and Biology (Fig. 1). These critical windows generally are very early in development, such as the A highly differentiated adult cell type or fetal or early postnatal periods, when the biological phenotype has been generated organ systems are rapidly developing and through a complex cascade of developmen- sensitive to subtle shifts in the epigenome.3 tal processes. The stem cell populations of These critical exposure windows allow an the embryo or selected tissues undergo a environmental factor or toxicant to per- cascade of genetic steps through cell fate manently modify an epigenome that then determinations, development of differen- continues throughout development to tiated cell types, organogenesis, specified impact genetic programming and result in physiological states and phenotypes. This a modified adult epigenome and genome genetic process includes classic transitions activity (transcriptome). This promotes in transcriptional control to lead to a cas- a susceptibility to develop disease or cre- Key words: epigenetic, transgenerational, cade of specific transcriptomes at each ates an increased biological variation in inheritance, mitotic, environmental, stage of development. This programmed phenotype that will facilitate an adapta- toxicants, evolution, disease etiology developmental process is hardwired and tion event and influence natural selection Submitted: 05/18/11 follows classic genetic processing. The (Fig. 1). genetic control of developmental biology is The stages or cascade of steps in both Revised: 05/19/11 stable and integrated into the overall phys- the genetics and epigenetics are highly DOI: 10.4161/epi.6.7.16537 iology and phenotype of the organism. In integrated and influence each other dur- Correspondence to: Michael K. Skinner; contrast to the genetic control of cellular ing the developmental process. Therefore, Email: [email protected] activity, the epigenetic cascade of events environmental epigenetics and genetics

838 Epigenetics Volume 6 Issue 7 POINT-OF-VIEW POINT-OF-VIEW

Figure 1. Integration epigenetics and genetics in development. should not be considered mutually exclu- germ cell is being reprogrammed at the disease states or phenotype be transmit- sive, but instead highly integrated and DNA methylation level.10 The environ- ted through the germ line in the absence dependent on each other. The genome mental toxicant alters the DNA methyla- of direct exposure.11 If direct exposure of DNA sequence provides the stable nature tion to generate new imprinted-like sites the environmental factor is involved then of an organism that is hardwired and that then are transmitted to subsequent this would simply be direct exposure toxi- programmed. The epigenome provides a generations through the germ line (sperm) cology. An example is exposure of a ges- more plastic molecular process4-6 that is (Fig. 2). All the somatic cells derived from tating female that has the F0 female, F1 responsive to the environment to impact this germ line will have a baseline shift in fetus and germ line within the fetus that biology, disease etiology and evolutionary their epigenome and, as the cells differ- will generate the F2 generation directly biology. Epigenetics and genetics should entiate, a corresponding shift in genome exposed.17 Therefore, an F3 generation is be considered cooperative and together activity and transcriptomes that in some required to assess a potential transgenera- provide a more complex and integrated tissues will promote disease states or phe- tional phenotype from a gestating female molecular mechanism for the control of notypic variation (Fig. 2).11 The transmis- exposure.17 In the event an adult male or development and biology. sion of any genetic or epigenetic molecular female is exposed, the F0 generation adult information between generations requires and the germ line that will generate the Environmental Epigenetic germ line transmission and permanent F1 generation are directly exposed, such Transgenerational Inheritance alterations in DNA sequence or the epig- that an F2 generation is required to obtain enome.11 Due to the reprogramming of an epigenetic transgenerational pheno- Epigenetic transgenerational inheritance the epigenome (DNA methylation) at fer- type.18 Although previous literature has requires germ line transmission of epigen- tilization,10,11 the modified epigenetic sites suggested transgenerational phenotypes in etic information between generations in will need to be imprinted-like to escape F1 or F2 generations, these studies often the absence of direct environmental expo- the demethylation process.3,8,11,12 The sug- had direct exposures involved so can not sures. During a critical window of germ gestion that an altered epigenome may be considered epigenetic transgenerational cell development, embryonic gonadal sex increase genomic instability and allow inheritance phenotypes, but direct expo- determination in mammals, environmen- genetic mutations to develop in subse- sure toxicology. Epigenetic transgenera- tal factors or toxicants have been shown to quent generations12 remains a possibility tional inheritance phenotypes require the influence epigenetic programming in the that needs to be investigated further.7 lack of direct exposure to be considered male germ line (sperm), which becomes A number of environmental factors and transgenerational. permanently programmed (imprinted),7 toxicants have now been shown to promote Environmentally induced epigenetic and then allows the transgenerational epigenetic transgenerational inheritance transgenerational inheritance has signifi- transmission of adult onset disease pheno- of disease states or phenotypic variation cant impacts in the areas of disease etiol- types.8,9 The general mechanism for this including the fungicide vinclozolin,8 ogy, inheritance of phenotypic variation epigenetic transgenerational inheritance plastic compound bisphenol A (BPA),13 and evolutionary biology. This phenom- in mammals involves exposure of a gestat- toxicant dioxin,14 stress responses15 and enon provides an alternate to genetic ing female during the period of gonadal nutrition.16 A critical factor in epigenetic Mendelian inheritance that can provide sex determination when the primordial transgenerational inheritance is that the a molecular mechanism for how the

www.landesbioscience.com Epigenetics 839 Figure 2. Scheme for epigenetic transgenerational inheritance. environment can influence disease etiol- The definition of “inheritance” is trans- population or associated physiology. The ogy and general biological phenotypes. mission of information between genera- ability to maintain a specific epigenome In regards to disease etiology, the familial tions of an organism, and is accepted by after mitosis is in part how different cell transmission or non-Mendelian charac- the public and general scientific commu- types maintain distinct differentiated teristics of a variety of disease states can nity as such. The ability of the epigenome states and facilitate a normal developmen- be explained. In regards to evolutionary to be replicated and transmitted upon tal process. biology, the ability to acquire an increased cellular proliferation through the mitotic The mechanisms involved in the rep- biological variation in phenotype follow- process is distinct and should be consid- lication of the epigenome during mitosis ing an ancestral environmental exposure ered “mitotic stability” not “inheritance”. are understood for DNA methylation will facilitate a potential adaptation event The use of the term epigenetic inheritance and small RNAs, but limited informa- to allow the natural selection process. has confused the scientific community tion exists for histone modifications and Environmental epigenetic transgenera- and public to consider germline-mediated chromatin structure. The DNA methyla- tional inheritance may provide a molecu- transgenerational phenomena, rather than tion marks are identified on the parental lar process to explain rapid evolutionary simply replication of the epigenome during DNA strand during S phase DNA synthe- events and how environment can influ- mitosis. Therefore, the proposal is made sis by DNA methyltransferase (DNMT), ence evolution. to define the replication of the epigenome which then methylates the newly synthe- during mitosis as “Mitotic Stability” and sized strand of DNA to replicate the DNA Somatic Epigenetic not refer to this as epigenetic inheritance. methylation pattern of the parental cell. Mitotic Stability The definition of epigenetics would be Therefore, the DNA methylation marks as previously described in reference 11, are replicated during mitosis to maintain In the 1940s, when Conrad Waddington “molecular factors or processes around the methylome. The non-coding RNAs described environment-gene interactions DNA that regulate genome activity inde- that act independent of DNA or RNA as epigenetics, he discussed the stable pendent of DNA sequence and that are sequences act as epigenetic components nature of epigenetics,4 but had no idea of mitotically stable.” to alter gene expression. The non-coding the molecular aspects of the phenomena. It The insight of Art Riggs to suggest RNA islands of DNA sequence are repli- was not until the 1970’s that DNA meth- the critical need for epigenetic marks to cated through normal DNA synthesis to ylation was described by Robin Holliday5 be replicated and stable during mitosis6,12 have mitotic stability of these non-coding and Art Riggs.6 Riggs discussed the stable was very significant and indeed allows RNAs. The histone modifications appear nature of the epigenetics as epigenetic epigenetics to have a profound biological to be replicated following mitosis but the inheritance following cell proliferation or impact. In the event the epigenome was molecular mechanism for replicating the mitosis.19 Unfortunately, this nomencla- not replicated during mitosis, epigenetics histone code is not known at present.20 ture of ‘inheritance’ is not accurate and would only impact the immediate cell and Similarly, replication of the chroma- misleading to suggest generational events. not have a long-term impact on the cell tin structure is known to occur, but the

840 Epigenetics Volume 6 Issue 7 basic replication molecular mechanism inclusion of epigenetics in our consider- to consider in evolutionary biology. remain to be elucidated.21 Therefore, fur- ation of basic developmental processes Previously, we have demonstrated an envi- ther research is needed to clarify the basic and physiology significantly expands our ronmental toxicant exposure during fetal molecular mechanisms involved in epi- ability to understand the systems biology gonadal sex determination can promote genetic mitotic stability. of the organism. The ability of the epig- epigenetic transgenerational inheritance Although the germ cell is critical enome to be replicated during somatic of altered sexual selection phenotypes.22 for transmission of genetic and epigen- cell mitosis also can explain how early life Since sexual selection is a major determi- etic information between generations, the exposures can program later life physiol- nant for natural selection, this experiment somatic cells of organism (non-germ cell ogy and adult onset disease. This is a new provides direct evidence that environmen- types) are essential for the basic devel- paradigm for disease etiology that needs tal epigenetic transgenerational inheri- opmental biology and physiology of an to be considered. Somatic cell epigenetic tance may have a role in evolution. This organism. Somatic cells are not capable of mitotic stability provides a somewhat per- does provide a “neo-Lamarckian influence transmitting information between genera- manent shift in the epigenome following to facilitate Darwinian evolution” concept tions, but have a critical role in the physi- an exposure during a critical window of for evolutionary biology. ology and disease states of the individual. development, such that later life physiol- The reviewed environmental epigenetic The reason epigenetic mitotic stability is ogy and disease can be linked (Fig. 1). transgenerational inheritance and somatic critical relates to the somatic cell differ- These somatic cell effects are likely epigenetic mitotic stability will both have entiation and function. In the event, as more common and critical for the individ- significant roles in development, physiol- shown in Figure 1, an environmental fac- ual exposed than epigenetic transgenera- ogy, disease and evolution. These molecu- tor modified the epigenome of a somatic tional inheritance of exposure phenotypes. lar mechanisms and an integration with cell during a critical window of develop- However, the germ line transmission of classic genetics are now required to more ment, the somatic epigenetic mitotic sta- a permanent shift in the epigenome will fully understand the systems biology of bility would replicate this epigenome and potentially impact all subsequent genera- development, physiology and disease, as permanently influence the somatic cell dif- tions to promote a phenotypic variation well as areas of biology such as evolution. ferentiation and function throughout life. and/or disease state (Fig. 2). Since all the Therefore, long after an early life expo- somatic cells generated from the germ line References sure, the modified epigenome will con- involved will have a shift in their epig- 1. Skinner MK. Role of epigenetics in developmental biology and transgenerational inheritance. Birth tinue to alter gene expression and that cell enomes and genome activity, the envi- Defects Res C Embryo Today 2011; 93:51-5. population. This provides a mechanism ronmental epigenetic transgenerational 2. Barker DJ. The developmental origins of adult dis- for the developmental origins of disease inheritance has a profound effect on biol- ease. J Am Coll Nutr 2004; 23:588-95. 3. Jirtle RL, Skinner MK. Environmental epigenom- to explain how a transient exposure early ogy and disease. In the case of disease ics and disease susceptibility. Nat Rev Genet 2007; in life can promote a susceptibility for dis- etiology this can explain non-Mendelian 8:253-62. 4. Waddington CH. The epigenotype. Endeavour 1942; ease later in life. The most critical molecu- inheritance of disease, environmentally 1:18-20. lar factor involved in this phenomenon is induced increases in disease frequency and 5. Holliday R, Pugh JE. DNA modification mecha- the somatic epigenetic mitotic stability. regional differences in disease frequencies. nisms and gene activity during development. Science 1975; 187:226-32. As previously discussed, the integration Clearly epigenetics will have a critical 6. Singer J, Roberts-Ems J, Riggs AD. Methylation of of the epigenome to genome activity and role in disease etiology and the amount mouse liver DNA studied by means of the restriction the mitotic stability of the epigenome on of adult onset disease associated with epi- enzymes msp I and hpa II. Science 1979; 203:1019-21. 7. Guerrero-Bosagna C, Settles M, Lucker BJ, Skinner somatic cells provides a molecular mecha- genetic transgenerational inheritance will MK. Epigenetic transgenerational actions of vinclo- nism for environment to influence disease need to be established. zolin on promoter regions of the sperm epigenome. etiology and phenotypic variation associ- In regards to environmentally induced PLoS One 2010; 5:13100. 8. Anway MD, Cupp AS, Uzumcu M, Skinner MK. ated with evolution. epigenetic transgenerational inheritance Epigenetic transgenerational actions of endocrine dis- of biological or phenotypic variation, a ruptors and male fertility. Science 2005; 308:1466-9. significant impact on evolutionary biology 9. Anway MD, Leathers C, Skinner MK. Endocrine Summary disruptor vinclozolin induced epigenetic transgen- 11 needs to be considered. An environmen- erational adult-onset disease. Endocrinology 2006; Epigenetics provides a molecular mecha- tal factor such as nutrition promoting a 147:5515-23. 10. Feng S, Jacobsen SE, Reik W. Epigenetic reprogram- nism for environmental factors (for exam- modification of germ line epigenetic pro- ming in plant and animal development. Science ple, nutrition) and toxicants to influence gramming that becomes permanently pro- 2010; 330:622-7. biology and disease. The integrated nature grammed (Fig. 2) will have a role in the 11. 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www.landesbioscience.com Epigenetics 841 14. Bruner-Tran KL, Osteen KG. Developmental expo- 17. Skinner MK. What is an epigenetic transgenerational 21. Georgatos SD, Markaki Y, Christogianni A, Politou sure to TCDD reduces fertility and negatively affects phenotype? F3 or F2. Reprod Toxicol 2008; 25:2-6. AS. Chromatin remodeling during mitosis: a struc- pregnancy outcomes across multiple generations. 18. Skinner MK. Metabolic disorders: Fathers’ nutri- ture-based code? Front Biosci 2009; 14:2017-27. Reprod Toxicol 2011; 31:344-50. tional legacy. Nature 2010; 467:922-3. 22. Crews D, Gore AC, Hsu TS, Dangleben NL, Spinetta 15. Matthews SG, Phillips DI. Transgenerational inheri- 19. Chen ZX, Riggs AD. Maintenance and regulation M, Schallert T, et al. Transgenerational epigenetic tance of stress pathology. Exp Neurol 2011; In press. of DNA methylation patterns in mammals. Biochem imprints on mate preference. Proc Natl Acad Sci USA 16. Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Cell Biol 2005; 83:438-48. 2007; 104:5942-6. Hanson MA, Lillycrop KA. Dietary protein restric- 20. Turner BM. Histone acetylation and an epigenetic tion of pregnant rats in the F0 generation induces code. Bioessays 2000; 22:836-45. altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 2007; 97:435-9.

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