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Background  Our independent cohort studies have consistently shown the reduction of the nuclear receptor RORA (retinoic acid-related orphan receptor-alpha) in lymphoblasts as well as in brain tissues from individuals with autism spectrum disorder (ASD). Moreover, we have found that RORA regulates the gene for aromatase, which converts androgen to estrogen, and that male and female hormones regulate  RORA  in opposite directions, with androgen suppressing RORA, suggesting that the sexually dimorphic regulation of  RORA  may contribute to the male bias in ASD. However, the molecular mechanisms through which androgen and estrogen differentially regulate  RORA  are still unknown.    Methods  Here we use functional knockdown of hormone receptors and coregulators with small interfering RNA (siRNA) to investigate their involvement in sex hormone regulation of  RORA  in human neuronal cells. Luciferase assays using a vector containing various  RORA  promoter constructs were first performed to identify the promoter regions required for inverse regulation of  RORA  by male and female hormones. Sequential chromatin immunoprecipitation methods followed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses of  RORA  expression in hormone-treated SH-SY5Y cells were then utilized to identify coregulators that associate with hormone receptors on the  RORA  promoter. siRNA-mediated knockdown of interacting coregulators was performed followed by qRT-PCR analyses to confirm the functional requirement of each coregulator in hormone-regulated  RORA  expression.    Results  Our studies demonstrate the direct involvement of androgen receptor (AR) and estrogen receptor (ER) in the regulation of RORA by male and female hormones, respectively, and that the promoter region between −10055 bp and −2344 bp from the transcription start site of  RORA  is required for the inverse hormonal regulation. We further show that AR interacts with SUMO1, a reported suppressor of AR transcriptional activity, whereas ERα interacts with the coactivator NCOA5 on the  RORA  promoter. siRNA-mediated knockdown of  SUMO1  and  NCOA5  attenuate the sex hormone effects on  RORA  expression.    Conclusions  AR and SUMO1 are involved in the suppression  RORA  expression by androgen, while ERα and NCOA5 collaborate in the up-regulation of  RORA  by estrogen. While this study offers a better understanding of molecular mechanisms involved in sex hormone regulation of  RORA , it also reveals another layer of complexity with regard to gene regulation in ASD. Inasmuch as coregulators are capable of interacting with a multitude of transcription factors, aberrant expression of coregulator proteins, as we have seen previously in lymphoblasts from individuals with ASD, may contribute to the polygenic nature of gene dysregulation in ASD.

Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism