A multidisciplinary team from the sex neuroscience group, made up of researchers from the Universidad Nacional de Educación a Distancia (UNED) and the University of A Coruña —including Drs. Antonio Guillamón, Rosa Fernández and Eduardo Pásaro— has published in Scientific Reports the first study that directly links the methylation status of the CBLL1 gene with cortical thickness in transgender individuals.
The study, cross-sectional and epigenome-wide association in design, included 22 transgender men who experienced gender dysphoria before starting gender affirming hormone treatment (GAHT), compared with 25 cisgender men and 28 cisgender women as comparison groups. Using the Infinium Human Methylation 850k array (Illumina), the full methylome of each participant was analyzed, and the methylation values were subsequently correlated with structural measures of the cerebral cortex obtained by magnetic resonance imaging.
The results showed that the CBLL1 and DLG1 genes presented a lower degree of methylation (hypomethylation) in transgender men compared with both cisgender groups. This hypomethylation correlated significantly with global and left-hemisphere cortical thickness. CBLL1 is abundantly expressed in the brain, with a particular concentration in the postsynaptic space of the cerebral cortex, which reinforces its functional relevance for cortical development.
For the authors, these findings support a neuroevolutionary hypothesis of gender identity: sexual differentiation of the brain depends on a network in which sex chromosomes, gonadal hormones and epigenetic mechanisms such as DNA and RNA methylation are involved. The cross-sectional design does not allow determining whether the hypomethylation of CBLL1 is a cause or a consequence of the dysphoria, nor the relative weight of internal (hormonal) or external (family and social) factors, but it opens a direct line of research into the molecular mechanisms underlying gender identity.
This work adds to the previous evidence from the same group, which had already described associations between methylation of the estrogen receptor alpha promoter (ESR1) and gender incongruence, consolidating epigenetics as a central axis for understanding the biological basis of gender dysphoria.
Bibliographic reference
Fernández R, Zubiaurre-Elorza L, Santisteban A, et al. CBLL1 is hypomethylated and correlates with cortical thickness in transgender men before gender affirming hormone treatment. Sci Rep. 2023;13(1):21609.
DOI: https://doi.org/10.1038/s41598-023-48782-2
PMID: 38062063
Publication access: the original reference can be consulted in open access or through the indicated DOI.
