Cyclical DNA Methyltransferase 3a Expression Is a Seasonal and Estrus Timer in Reproductive Tissues

Eloise W. J. Lynch, Chris S. Coyle, Marlene Lorgen, Ewan M. Campbell, Alan S. Bowman, Tyler J. Stevenson

Research output: Contribution to journalArticle

10 Citations (Scopus)
5 Downloads (Pure)

Abstract

It is becoming clear that epigenetic modifications such as DNA methylation can be dynamic and in many cases, reversible. Here, we investigated the photoperiod and hormone regulation of DNA methylation in testes, ovaries and uterine tissue across multiple time scales. We hypothesized that DNA methyltransferase 3a (dnmt3a) is driven by photoperiodic treatment, exhibits natural variation across the female reproductive cycle and that melatonin increases whereas estrogen reduces DNA methylation. We used Siberian hamsters (Phodopus sungorus) due to their robust changes in reproductive physiology across seasonal and oestrus time scales. Our findings indicate that short day (SD) – winter like conditions significantly increased global DNA methylation and dnmt3a expression in the testes. Using immunohistochemistry, we confirm that increased dnmt3a expression was primarily localized to spermatogonium. Conversely, the ovaries did not exhibit variation in DNA methylation or dnmt3a/3b expression. However, exposure to SD significantly increased uterine dnmt3a expression. We then determined that dnmt3a was significantly decreased during the oestrus stage. Next, we ovariectomized females and subsequently identified that a single estrogen+progesterone injection was sufficient to rapidly inhibit dnmt3a and dnmt3b expression. Finally, we demonstrate that treatment of HEK293 cells with melatonin significantly increased both dnmt3a and dnmt3b expression suggesting that long-duration nocturnal signalling in SD may be involved in the regulation of DNA methylation in both sexes. Overall, our data indicate that dnmt3a shows marked photoperiod and oestrus plasticity that likely has broad downstream effects on the timing of the genomic control of reproductive function.
Original languageEnglish
Pages (from-to)2469 –2478
Number of pages10
JournalEndocrinology
Volume157
Issue number6
Early online date22 Apr 2016
DOIs
Publication statusPublished - 1 Jun 2016

Fingerprint

Estrus
DNA Methylation
Phodopus
Photoperiod
Melatonin
Testis
Ovary
Estrogens
DNA methyltransferase 3A
Spermatogonia
HEK293 Cells
Epigenomics
Progesterone
Immunohistochemistry
Hormones
Injections
Therapeutics

Cite this

Cyclical DNA Methyltransferase 3a Expression Is a Seasonal and Estrus Timer in Reproductive Tissues. / Lynch, Eloise W. J.; Coyle, Chris S.; Lorgen, Marlene; Campbell, Ewan M.; Bowman, Alan S.; Stevenson, Tyler J.

In: Endocrinology, Vol. 157, No. 6, 01.06.2016, p. 2469 –2478.

Research output: Contribution to journalArticle

@article{59c8537d22044ede94283ba26d7ab8dd,
title = "Cyclical DNA Methyltransferase 3a Expression Is a Seasonal and Estrus Timer in Reproductive Tissues",
abstract = "It is becoming clear that epigenetic modifications such as DNA methylation can be dynamic and in many cases, reversible. Here, we investigated the photoperiod and hormone regulation of DNA methylation in testes, ovaries and uterine tissue across multiple time scales. We hypothesized that DNA methyltransferase 3a (dnmt3a) is driven by photoperiodic treatment, exhibits natural variation across the female reproductive cycle and that melatonin increases whereas estrogen reduces DNA methylation. We used Siberian hamsters (Phodopus sungorus) due to their robust changes in reproductive physiology across seasonal and oestrus time scales. Our findings indicate that short day (SD) – winter like conditions significantly increased global DNA methylation and dnmt3a expression in the testes. Using immunohistochemistry, we confirm that increased dnmt3a expression was primarily localized to spermatogonium. Conversely, the ovaries did not exhibit variation in DNA methylation or dnmt3a/3b expression. However, exposure to SD significantly increased uterine dnmt3a expression. We then determined that dnmt3a was significantly decreased during the oestrus stage. Next, we ovariectomized females and subsequently identified that a single estrogen+progesterone injection was sufficient to rapidly inhibit dnmt3a and dnmt3b expression. Finally, we demonstrate that treatment of HEK293 cells with melatonin significantly increased both dnmt3a and dnmt3b expression suggesting that long-duration nocturnal signalling in SD may be involved in the regulation of DNA methylation in both sexes. Overall, our data indicate that dnmt3a shows marked photoperiod and oestrus plasticity that likely has broad downstream effects on the timing of the genomic control of reproductive function.",
author = "Lynch, {Eloise W. J.} and Coyle, {Chris S.} and Marlene Lorgen and Campbell, {Ewan M.} and Bowman, {Alan S.} and Stevenson, {Tyler J.}",
note = "Acknowledgments We thank Gerald Lincoln for his critical feedback on a previous version of this manuscript. Author contributions included the following: T.J.S. conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. E.W.J.L. conducted the experiments and analyzed the data. C.S.C. conducted the immunocytochemistry. M.L. conducted the HEK293 cell culture assays. E.M.C. and A.S.B. provided technical assistance. This work was supported by the University of Aberdeen College of Life Sciences and Medicine grant (to T.J.S.). E.W.J.L. was supported by a Society for Reproduction and Fertility undergraduate scholarship. Disclosure Summary: The authors have nothing to disclose.",
year = "2016",
month = "6",
day = "1",
doi = "10.1210/en.2015-1988#sthash.X35973Kb.dpuf",
language = "English",
volume = "157",
pages = "2469 –2478",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "6",

}

TY - JOUR

T1 - Cyclical DNA Methyltransferase 3a Expression Is a Seasonal and Estrus Timer in Reproductive Tissues

AU - Lynch, Eloise W. J.

AU - Coyle, Chris S.

AU - Lorgen, Marlene

AU - Campbell, Ewan M.

AU - Bowman, Alan S.

AU - Stevenson, Tyler J.

N1 - Acknowledgments We thank Gerald Lincoln for his critical feedback on a previous version of this manuscript. Author contributions included the following: T.J.S. conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. E.W.J.L. conducted the experiments and analyzed the data. C.S.C. conducted the immunocytochemistry. M.L. conducted the HEK293 cell culture assays. E.M.C. and A.S.B. provided technical assistance. This work was supported by the University of Aberdeen College of Life Sciences and Medicine grant (to T.J.S.). E.W.J.L. was supported by a Society for Reproduction and Fertility undergraduate scholarship. Disclosure Summary: The authors have nothing to disclose.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - It is becoming clear that epigenetic modifications such as DNA methylation can be dynamic and in many cases, reversible. Here, we investigated the photoperiod and hormone regulation of DNA methylation in testes, ovaries and uterine tissue across multiple time scales. We hypothesized that DNA methyltransferase 3a (dnmt3a) is driven by photoperiodic treatment, exhibits natural variation across the female reproductive cycle and that melatonin increases whereas estrogen reduces DNA methylation. We used Siberian hamsters (Phodopus sungorus) due to their robust changes in reproductive physiology across seasonal and oestrus time scales. Our findings indicate that short day (SD) – winter like conditions significantly increased global DNA methylation and dnmt3a expression in the testes. Using immunohistochemistry, we confirm that increased dnmt3a expression was primarily localized to spermatogonium. Conversely, the ovaries did not exhibit variation in DNA methylation or dnmt3a/3b expression. However, exposure to SD significantly increased uterine dnmt3a expression. We then determined that dnmt3a was significantly decreased during the oestrus stage. Next, we ovariectomized females and subsequently identified that a single estrogen+progesterone injection was sufficient to rapidly inhibit dnmt3a and dnmt3b expression. Finally, we demonstrate that treatment of HEK293 cells with melatonin significantly increased both dnmt3a and dnmt3b expression suggesting that long-duration nocturnal signalling in SD may be involved in the regulation of DNA methylation in both sexes. Overall, our data indicate that dnmt3a shows marked photoperiod and oestrus plasticity that likely has broad downstream effects on the timing of the genomic control of reproductive function.

AB - It is becoming clear that epigenetic modifications such as DNA methylation can be dynamic and in many cases, reversible. Here, we investigated the photoperiod and hormone regulation of DNA methylation in testes, ovaries and uterine tissue across multiple time scales. We hypothesized that DNA methyltransferase 3a (dnmt3a) is driven by photoperiodic treatment, exhibits natural variation across the female reproductive cycle and that melatonin increases whereas estrogen reduces DNA methylation. We used Siberian hamsters (Phodopus sungorus) due to their robust changes in reproductive physiology across seasonal and oestrus time scales. Our findings indicate that short day (SD) – winter like conditions significantly increased global DNA methylation and dnmt3a expression in the testes. Using immunohistochemistry, we confirm that increased dnmt3a expression was primarily localized to spermatogonium. Conversely, the ovaries did not exhibit variation in DNA methylation or dnmt3a/3b expression. However, exposure to SD significantly increased uterine dnmt3a expression. We then determined that dnmt3a was significantly decreased during the oestrus stage. Next, we ovariectomized females and subsequently identified that a single estrogen+progesterone injection was sufficient to rapidly inhibit dnmt3a and dnmt3b expression. Finally, we demonstrate that treatment of HEK293 cells with melatonin significantly increased both dnmt3a and dnmt3b expression suggesting that long-duration nocturnal signalling in SD may be involved in the regulation of DNA methylation in both sexes. Overall, our data indicate that dnmt3a shows marked photoperiod and oestrus plasticity that likely has broad downstream effects on the timing of the genomic control of reproductive function.

U2 - 10.1210/en.2015-1988#sthash.X35973Kb.dpuf

DO - 10.1210/en.2015-1988#sthash.X35973Kb.dpuf

M3 - Article

VL - 157

SP - 2469

EP - 2478

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 6

ER -