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At the frontier of epigenetics of brain sex differences.

McCarthy MM, Nugent BM - Front Behav Neurosci (2015)

Bottom Line: The notion that epigenetics may play an important role in the establishment and maintenance of sex differences in the brain has garnered great enthusiasm but the reality in terms of actual advances has been slow.The majority of emphasis has been on candidate genes such as steroid receptors.Only recently have more generalized survey type approaches been achieved and these promise to open new vistas and accelerate discovery of important roles for DNA methylation, histone modification, genomic imprinting and microRNAs (miRs).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Maryland School of Medicine Baltimore, MD, USA.

ABSTRACT
The notion that epigenetics may play an important role in the establishment and maintenance of sex differences in the brain has garnered great enthusiasm but the reality in terms of actual advances has been slow. Two general approaches include the comparison of a particular epigenetic mark in males vs. females and the inhibition of key epigenetic enzymes or co-factors to determine if this eliminates a particular sex difference in brain or behavior. The majority of emphasis has been on candidate genes such as steroid receptors. Only recently have more generalized survey type approaches been achieved and these promise to open new vistas and accelerate discovery of important roles for DNA methylation, histone modification, genomic imprinting and microRNAs (miRs). Technical challenges abound and, while not unique to this field, will require novel thinking and new approaches by behavioral neuroendocrinologists.

No MeSH data available.


Related in: MedlinePlus

DNA methylation maintains feminization of brain and behavior. Conditional knockout of DNMT3a in the POA of mice demonstrated that reduced DNA methylation outside the critical period could still lead to masculinization of behavior, while treatment with exogenous estradiol could not. This was also found to be true in rats using DNMT inhibitors. During the critical period estradiol reduces DNMT activity but this effect is lost outside of the critical period. Thus the ongoing maintenance of DNA methylation appears essential for continued feminization. These observations reveal a novel source of plasticity in sexually dimorphic behavior.
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Figure 5: DNA methylation maintains feminization of brain and behavior. Conditional knockout of DNMT3a in the POA of mice demonstrated that reduced DNA methylation outside the critical period could still lead to masculinization of behavior, while treatment with exogenous estradiol could not. This was also found to be true in rats using DNMT inhibitors. During the critical period estradiol reduces DNMT activity but this effect is lost outside of the critical period. Thus the ongoing maintenance of DNA methylation appears essential for continued feminization. These observations reveal a novel source of plasticity in sexually dimorphic behavior.

Mentions: The end of the sensitive period for sexual differentiation is defined as the developmental age at which exogenous hormone treatment is no longer capable of masculinizing females. But why females lose sensitivity to the masculinizing effects of steroids was unknown. We mapped the level of DNMT activity in the POA of males and females from birth to 2 weeks of age and determined that females had significantly higher enzymatic activity during the first few days after birth but that by 4 days of age levels had equalized and by 1 week levels dropped precipitously in both sexes. Thus it appears the first few days of life are highly dynamic for DNMT activity in the POA. Further, treating neonatal females with a masculinizing dose of estradiol reduced DNMT activity to male-like levels, suggesting that at least one mechanism for estradiol mediated masculinization of the POA is via control of DNMT activity. In order to determine if DNA methylation past the sensitive period was required to maintain feminization of brain and behavior, we treated 10-day-old females with DNMT inhibitor and raised them to adulthood. We also treated some females with a masculinizing dose of estradiol at the same time and found that as adults, these females were not masculinized, (i.e., they were outside the sensitive period at this time) but their littermates that had been treated with DNMT inhibitor were masculinized. We observed a similar phenomenon in mice in which the DNMT3a gene was conditionally ablated in the developing POA by an adeno-associated virus (AAV)-Cre mediated knockout. All female DNMT3a floxed mice that received AAV-Cre displayed male sexual behaviors compared to very few control females. However, knockout did not occur until outside the sensitive period (Figure 5). Collectively these data indicate that the end of the sensitive period is a function of the loss of inhibition of DNMT activity by estradiol. How this occurs, from a mechanistic viewpoint, is unknown, as is why DNMT activity drops so markedly at the end of the first week of life. There is much still to be learned regarding the DNA methylome and sexual differentiation of brain and behavior.


At the frontier of epigenetics of brain sex differences.

McCarthy MM, Nugent BM - Front Behav Neurosci (2015)

DNA methylation maintains feminization of brain and behavior. Conditional knockout of DNMT3a in the POA of mice demonstrated that reduced DNA methylation outside the critical period could still lead to masculinization of behavior, while treatment with exogenous estradiol could not. This was also found to be true in rats using DNMT inhibitors. During the critical period estradiol reduces DNMT activity but this effect is lost outside of the critical period. Thus the ongoing maintenance of DNA methylation appears essential for continued feminization. These observations reveal a novel source of plasticity in sexually dimorphic behavior.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543874&req=5

Figure 5: DNA methylation maintains feminization of brain and behavior. Conditional knockout of DNMT3a in the POA of mice demonstrated that reduced DNA methylation outside the critical period could still lead to masculinization of behavior, while treatment with exogenous estradiol could not. This was also found to be true in rats using DNMT inhibitors. During the critical period estradiol reduces DNMT activity but this effect is lost outside of the critical period. Thus the ongoing maintenance of DNA methylation appears essential for continued feminization. These observations reveal a novel source of plasticity in sexually dimorphic behavior.
Mentions: The end of the sensitive period for sexual differentiation is defined as the developmental age at which exogenous hormone treatment is no longer capable of masculinizing females. But why females lose sensitivity to the masculinizing effects of steroids was unknown. We mapped the level of DNMT activity in the POA of males and females from birth to 2 weeks of age and determined that females had significantly higher enzymatic activity during the first few days after birth but that by 4 days of age levels had equalized and by 1 week levels dropped precipitously in both sexes. Thus it appears the first few days of life are highly dynamic for DNMT activity in the POA. Further, treating neonatal females with a masculinizing dose of estradiol reduced DNMT activity to male-like levels, suggesting that at least one mechanism for estradiol mediated masculinization of the POA is via control of DNMT activity. In order to determine if DNA methylation past the sensitive period was required to maintain feminization of brain and behavior, we treated 10-day-old females with DNMT inhibitor and raised them to adulthood. We also treated some females with a masculinizing dose of estradiol at the same time and found that as adults, these females were not masculinized, (i.e., they were outside the sensitive period at this time) but their littermates that had been treated with DNMT inhibitor were masculinized. We observed a similar phenomenon in mice in which the DNMT3a gene was conditionally ablated in the developing POA by an adeno-associated virus (AAV)-Cre mediated knockout. All female DNMT3a floxed mice that received AAV-Cre displayed male sexual behaviors compared to very few control females. However, knockout did not occur until outside the sensitive period (Figure 5). Collectively these data indicate that the end of the sensitive period is a function of the loss of inhibition of DNMT activity by estradiol. How this occurs, from a mechanistic viewpoint, is unknown, as is why DNMT activity drops so markedly at the end of the first week of life. There is much still to be learned regarding the DNA methylome and sexual differentiation of brain and behavior.

Bottom Line: The notion that epigenetics may play an important role in the establishment and maintenance of sex differences in the brain has garnered great enthusiasm but the reality in terms of actual advances has been slow.The majority of emphasis has been on candidate genes such as steroid receptors.Only recently have more generalized survey type approaches been achieved and these promise to open new vistas and accelerate discovery of important roles for DNA methylation, histone modification, genomic imprinting and microRNAs (miRs).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Maryland School of Medicine Baltimore, MD, USA.

ABSTRACT
The notion that epigenetics may play an important role in the establishment and maintenance of sex differences in the brain has garnered great enthusiasm but the reality in terms of actual advances has been slow. Two general approaches include the comparison of a particular epigenetic mark in males vs. females and the inhibition of key epigenetic enzymes or co-factors to determine if this eliminates a particular sex difference in brain or behavior. The majority of emphasis has been on candidate genes such as steroid receptors. Only recently have more generalized survey type approaches been achieved and these promise to open new vistas and accelerate discovery of important roles for DNA methylation, histone modification, genomic imprinting and microRNAs (miRs). Technical challenges abound and, while not unique to this field, will require novel thinking and new approaches by behavioral neuroendocrinologists.

No MeSH data available.


Related in: MedlinePlus