A talented team from the University of Maryland has added some strong molecular evidence that DNA methylation is an active player in setting the sexual behaviors you’re born with.

Sexuality has always been a complex topic. Typically it refers to presence or absence of certain sex organs. However, the concept of gender is more complex, as research suggests that a brain can indeed be hardwired for the behaviour of a gender that is ‘opposite’ to that sex’s standard behaviour. During typical mammalian neurodevelopment all brains are destined for a feminized phenotype unless they are exposed to gonadal hormones during a critical window of development.

By examining and/or manipulating the DNAm patterns in rodents the team found:

Gonadal steroids create sex differences by primarily acting in a brain region known as preoptic area (POA).

The POA shows high levels of sexual dimorphism, where DNMT activity is significantly lower in male neonates.

The primary function of the masculinizing steroid, estradiol, in the POA is to reduce DNMT activity, thereby decreasing global DNA methylation and “releasing masculinizing genes from epigenetic repression”.

This results in functional phenotype by increasing dendritic spine density (the brain cells receiving connectors) in the POA and masculinizing sexual behaviour of female mice.

Inhibiting DNMTs pharmacologically mimics estradiol and masculinizes brain markers and sex behaviour in female rats.

Conditionally knocking out the de novo writer, Dnmt3a, produces the same chain of events and masculinizing behaviors in female mice.

Using RNA-seq the team found that while there were fewer differences than expected, some gene expression and isoform variant choice are modulated by the established DNA methylation.

These findings cast doubts on previous theories of gender about how sex differences in the brain are established. It was once believed to only be able to set during very narrow critical periods and also suggested that steroids directly act as transcription factors. Ultimately, this report provides a more dynamic model of gender. If this holds true in humans, it offers a new avenue of investigation to the neurodevelopmental theory that feminine identity is the default state and provides a molecular mechanism where the interaction of gonadal hormones with DNA methylation machinery unleashes a masculine identity.

Lead author Bridget Nugent shares that:

“Uncovering the basic mechanisms that program male and female-specific gene expression and give rise to sex differences in neural patterning is essential to understanding the biological basis of behaviors that are critical to an animal’s survival and reproductive fitness, such as sexual, parental, and aggressive behaviors. Further, elucidating the biological underpinnings of sex differences in the brain will one day help us better understand the etiology of sex differences in psychiatric and neurological disorders in humans. My hope is that these studies have taken us one step closer to fully understanding how and why males and females are so different. In this paper, we’ve shown a mechanism whereby hormones create sex differences in the developing brain: by producing sex-specific patterns of DNA methylation. Maintenance of the DNA methylation patterns established during sexual differentiation of the brain appears to be necessary to sustain the brain’s differentiated state.”

Find out the intimate details about how DNA methylation makes female the default at Nature Neuroscience, March 2015