title: Sex-Specific Effects of Testosterone on the Sexually Dimorphic Transcriptome and Epigenome of Embryonic Neural Stem/Progenitor Cells.
abstract: The mechanisms by which sex differences in the mammalian brain arise are poorly understood, but are influenced by a combination of underlying genetic differences and gonadal hormone exposure. Using a mouse embryonic neural stem cell (eNSC) model to understand early events contributing to sexually dimorphic brain development, we identified novel interactions between chromosomal sex and hormonal exposure that are instrumental to early brain sex differences. RNA-sequencing identified 103 transcripts that were differentially expressed between XX and XY eNSCs at baseline (FDR = 0.10). Treatment with testosterone-propionate (TP) reveals sex-specific gene expression changes, causing 2854 and 792 transcripts to become differentially expressed on XX and XY genetic backgrounds respectively. Within the TP responsive transcripts, there was enrichment for genes which function as epigenetic regulators that affect both histone modifications and DNA methylation patterning. We observed that TP caused a global decrease in 5-methylcytosine abundance in both sexes, a transmissible effect that was maintained in cellular progeny. Additionally, we determined that TP was associated with residue-specific alterations in acetylation of histone tails. These findings highlight an unknown component of androgen action on cells within the developmental CNS, and contribute to a novel mechanism of action by which early hormonal organization is initiated and maintained.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Bramble
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Roach
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Lipson
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Neerja
authors.initials: N
authors.lastname: Vashist
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Ascia
authors.initials: A
authors.lastname: Eskin
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Tuck
authors.initials: T
authors.lastname: Ngun
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gosschalk
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Hayk
authors.initials: H
authors.lastname: Barseghyan
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.|Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Arboleda
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D019070:Cell Lineage / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D017423:Sequence Analysis, RNA; D012727:Sex Characteristics; D012730:Sex Chromosomes; D013739:Testosterone / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D006657:Histones; D013739:Testosterone; D012313:RNA