Part 2: Epigenetic Regulation

In PART 1 we defined the Epigenome and discussed the Epigenetic process.  In part 2, we’ll explore Regulatory Mechanisms responsible for gene modification and expression.  At the conclusion we will speculate on the implications these processes may have on the Transgender brain.


Established research has concluded that the human brain develops as feminine, and only when acted up on by gonadal hormones, does gender identity begin to develop.  Mila Madison, has explored the developing brain in her article, “Origins of the Transgender Condition,” for TransgenderUniverse.   Gonadal hormones are steroidal hormones that stimulate reproductive organs and secondary sex characteristics, during the perinatal developmental stage.  Estradiol, Progesterone and Testosterone are the steroid hormones responsible for these developmental changes.  These steroids act on enzymes and proteins on the genome and the epigenome, and these affects may hold the key to understanding how the transgender brain develops.

Principle Mechanisms

Three discovered processes of epigenetic modification are DNA methylation, histones modification, and RNA interference.

DNA Methylation

chromation structureDNA and the interaction of the protein chromatin, define what the DNA Methylation factors are within the cell nucleus.  This process is factored by the interaction of the genome and the environment.  This is an epigenetic tool used in gene expression to turn ‘off’ or silence genes.  Scientists have also discovered that DNA methylation is responsible for, among other things, X chromosome silencing, genomic imprinting, and chromosome stability.  Conversely, they have also discovered that errors in the process are responsible for negative consequences of organismal development, focally on diseases at present.DNAmethylation

De novo replication of the genome is not possible, strictly inclusive of the DNA strand, without the interaction of the epigenome.  The Epigenome’s heritable traits are the set of instructions that give a cell its identity.  If the chromatin protein is affected, DNA Methylation instructions, may combine to incorrect histone ‘tails’.  These N-terminal tails extend beyond the structure of the chromosome waiting specific post-translational modifications.  A hypothesis might be that gender identifiable instructions may cross, drop, or otherwise miscommunicate causing epigenetic tag errors, contributing to a gender dysphoric condition.

Histone modifications result from biological processes, which lead to the addition of specific marks on individual animo acids

Histone Tagging

Histones are proteins within the nucleus that compress the DNA.  Modification of histones is a method for epigenetic tagging of the genome.  Four proteins comprise the histone core within the nucleosome; H2A, H2B, H3, H4.  Along with thistone mechanisimshe linker histone, H1, these five proteins formulate the Chromatin building blocks.  There are presently six modifications for histone tagging; Acetylation, Histone Modification, Phosphorylation, Ubiquitylation,, Sumoylation, and Biotinylation.  All of which can serve as epigenetic tags, but we’ll highlight the first three for our purposes. For specific histone sites, enzymes and functions, consult this Histone Modification Table.

Acetylation: An important protein modification on histones in the field of epigenetics.  This process takes place as a co-translational and a post-translational modification, where the co-transational modification happens simultaneously with the translation of the mRNA.  The post-translational process involves modification of associated proteins prior to the mature protein formulation.  Where this process is most intriguing is on the Acetylation of the P53 protein.

P53 is known as the “guardian of the genome.”  It is responsible for gene stability and cellular regulation.  If P53 protein is not properly modified, a negative apoptic condition can result.  Apopsis is the programmed conditioning of cell death.  For example, the intentional separation of the fingers and toes,and the separation of the left and right brain hemispheres.

Observations of the thickness of separation differs in males and females.  Hypothetically, than, the abnormal modification of the P53 protein can alter this dependent separation, resulting in the blending of a male/female brain separation, giving rise to the developing transgender brain.

Phosphorylation: Is a post-translational modification process whereby enzymes are switched off or on.  This process also acts upon the P53 protein.  These complex signaling pathways are difficult for scientists to trace.  Different protein interactions can differ from pathway to pathway.  Enlisting Epidermal Growth Factors, changes have been tracked over time.  Where this becomes interesting is that testosterone is stimulated by epidermal growth factors, and epidermal growth factors are responsible for cell differentiation and growth.  It is possible, than, as the testosterone is introduced into the developing feminine brain, protein interactions are curtailed and pathways crossed, lost, or otherwise interrupted.  These modifications could in variably result in development of an intermixed Cerebral Cortex, Hypothalamus, and Corpus Callosum, all areas which are loosely speculated to be involved with gender identity(caveat: science has not identified where gender arises at this time).

Histone Methylation: Is a modification process affecting the nucleosome proteins H2A, H2B, H3, H4.  This modification may be responsible for protein transcription repression or protein activation.  Acting on chromatin, this modification process stimulates the neural development, is responsible for forming the bases for learning and long-term memory, as well as intellectual ability/disability.  Chromatin modification in this way, affects the gene transcription process.

histones imageMethylation of the histone is important in the development of the heterochromatin mechanism.  Histone Methyltransferases(HRTs) affect changes on the histone and effect cell changes when methyls are added.  Changes that are made to the heterochromatin mechanism and gene boundaries are passed down through epigenetics.

Females have XX chromosomes and males are XY.  The female embryo contains 2 X chromosomes, and the paternal X chromosome is rendered inactive through histone methylation.  Lysine is essential for histone methylation, and is responsible for tightly packing the inactive X chromosome into heterochromatin.  Lysine in not manufactured in the human body, therefore must be obtained solely through diet.  Therefore, it is conceivably possible, if the packed X chromosome retains some activity, then a more predominantly female embryo could develop.  Suggesting such a scenario, than a ‘feminized’ masculine brain could develop, lending to male gender dysphoria.

RNAi interference
RNA Interference

RNA affected is “non-coding RNA (ncRNA)-associated gene silencing are currently considered to initiate and sustain epigenetic change.”(Egger G. et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457-463 (2004) ).

During this biological process(RNAi), gene expression is inhibited by RNA molecules and genes are turned off, or ‘silenced’.  Through the action of double-stranded ribonucleic acid(RNA) molecules, microRNA(miRNA) and small interfering RNA(siRNA), messenger RNA(mRNA) molecules are destroyed.

This ‘interference’, is involved in the formation of histone epigenetic tagging and heterochromatin.  Any genetic disruption of this process weakens, or relaxes, the heterochromatin.  Relaxing the heterochromatin can decrease histone methylation, leading to erroneous expression of silenced genes of facultative chromatin in vivo transcription.

We can speculate that relaxing the chromatin could have conflicting affects in the developing embryo.  Potentially blending enzymes from the packed X chromosome with the developing unpacked X chromosome, which could lead to an infusion of paternal X-factors, diluting the effectiveness of testosterone.

Speculation on being Transgender

There are no clear identifying characteristics of gene expression or modification clearly pointing to what causes a brain to develop with a gender identity, nor a dysphoric gender identity.  It is intriguing, however, that Histone Methyltransferases(HRTs) are affected when methyls are added, and Hormone Replacement Therapy(HRT) also involves a methylation process.

We can clearly extrapolate on the complex developmental process the genome and epigenome collude to create.  Starting with viable hypotheses and from the data highlighted above, logical arguments have been postulated.  Researchers from University of Maryland School of Medicine may have made a crucial first step toward that understanding, however.

What ethical consequences arise if science does determine what processes determine gender identity?


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