ESPEYB16 6. DSD and Gender Dysphoria New Functions of (Old) Genes (5 abstracts)
6.2. Epigenetic repression of androgen receptor transcription in mutation-negative androgen insensitivity syndrome (AIS type II)
Hornig NC , Rodens P , Dörr H , Hubner NC , Kulle AE , Schweikert HU , Welzel M , Bens S , Hiort O , Werner R , Gonzalves S , Eckstein AK , Cools M , Verrijn-Stuart A , Stunnenberg HG , Siebert R , Ammerpohl O & Holterhus PM
J Clin Endocrinol Metab. 2018 Dec 1;103(12):4617–4627.
doi: 10.1210/jc.2018-00052. PMID: 30124873
This study shows for the first time that epigenetic changes in the androgen receptor gene (AR) proximal promoter region may underlie a clinical phenotype of Androgen Insensitivity Syndrome (AIS) in individuals in whom no DNA sequence mutation in AR or its promotor were found.
In their previous work, the authors demonstrated reduced AR activity in a subset of undervirilised AR-mutation negative individuals with clinical AIS. They termed this new clinical entity ‘AIS type II’. Here, they quantified AR mRNA and AR proximal promoter CpG methylation levels in genital skin fibroblasts of individuals with AIS type II and controls. They demonstrate, by a series of inventive and well-built experiments, that over half of AIS type II cases may be caused by epigenetic changes, i.e. increased methylation of specific CpG groups within the proximal AR promoter region. Increased methylation at two consecutive sites of this region was associated with decreased AR mRNA and protein levels in genital skin fibroblasts of patients as compared to controls. They were able to corroborate their findings by in vitro experiments, showing that methylation of a construct containing these CpGs resulted in reduced activation of a reporter gene. Lastly, they identified RUNX1 as a synergistically acting repressor of AR transcription.
Taken together, these data suggest that hypermethylation of the AR promoter leads to recruitment of several chromatin modifiers that ultimately induce chromatin compaction and hence inhibit gene transcription.
Volume 16
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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