An Analysis of the Implication of Estrogens and Steroid Receptor Coactivators in the Genetic Basis of Gender Incongruence

Abstract

In mammals, sex differences in the adult brain are established very early in development, when the brain is still very immature. In the case of having inherited the SRY gene, during embryogenesis, testosterone secreted by the testes enters the brain and is converted to estradiol by the aromatase. Then the estradiol acts by binding to intracellular estrogen receptors (ERs) located predominantly in neurons, masculinizing specific brain regions. But ERs are also transcription factors that, when they are exposed to their ligand, dimerize and form complexes with coactivator proteins and corepressors, modifying the transcription of multiple target genes in a cascade effect and ultimately neuronal function. Given the intimate relationship between steroids and brain dimorphism, and steroid coactivators and gene transcription, in the present work, we further explore the implication of ERs α and β, and steroid coactivators NCoA-1, NCoA-2, NCoA-3, NCoA-4, NCoA-5 and p300-CREBBP, in the genesis of brain dimorphism. Based on our data, we believe that the coactivators NCOA-1, NCOA-2 and p300-CREBBP could be considered as candidate genes for GI.

Epigenetics Is Implicated in the Basis of Gender Incongruence: An Epigenome-Wide Association Analysis

“…Gene ontology annotations related to this gene include chromatin binding and transcription coactivator activity. Besides that, previous DNA analysis of polymorphisms related to SRC-1 and SRC-2 coactivators have pointed out their possible implication in the process of brain dimorphism ( Fernández et al, 2021 ).…”

“…Some authors found variations in the DNA sequence of the androgen (AR) and estrogen (ERs, α and β) ( Henningsson et al, 2005 ; Hare et al, 2009 ; Fernández et al, 2014a , b , 2016 , 2018 , 2020a ; Cortés-Cortés et al, 2017 ; Foreman et al, 2019 ) that could hypothetically modulate the sensitivity of the nuclear steroid receptors. Furthermore, since AR and ER (α and β) are, at the same time, hormonal receptors and transcription factors, the modulation of gene expression via activation of AR and ERs by their ligands and coactivators, could be another presumptive mechanism underlying GI ( Fernández et al, 2021 ; Ramírez et al, 2021 ).…”

Gene Variants and Epigenetics That Lead to Gender Dysphoria

“…This gene's associated Gene Ontology annotations include chromatin binding and transcription coactivator activity [11,32]. In addition, earlier DNA studies of SRC-1 and SRC-2 coactivator polymorphisms have suggested their alleged role in the process of brain dimorphism [7,8]. In addition, mouse studies reveal that the protein produced by the gene ABT1 activates basal transcription from class II promoters by interacting with the DNA of class II promoters [11].…”

“…In addition, mouse studies reveal that the protein produced by the gene ABT1 activates basal transcription from class II promoters by interacting with the DNA of class II promoters [11]. The GO annotations associated with this gene are transcription coactivator activity, DNA binding, RNA binding, control of transcription by RNA polymerase II, and transcription coactivator activity [8,34]. In contrast, when comparing cis women to trans men, significant methylation appeared in only two CpGs, neither of which were islands [35,36].…”

“…Diagnostic and Statistical Manual of Mental disorders defines gender dysphoria as a "marked incongruence between their experienced or expressed gender and the one they were assigned at birth" [1,6]. According to the International Classification of Diseases ICD-11, gender incongruence (GI) is an incongruence between the individual's assigned sex and their experiences of gender [7,8]. Individuals with gender incongruence who experience difficulties or significant burdens might develop gender dysphoria [7,9].…”