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Background Prenatal exposure to androgens during brain development in male individuals may participate to increase their susceptibility to develop neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability. However, little is known about the action of androgens in human neural cells. Methods We used human neural stem cells differentiated from embryonic stem cells to investigate targets of androgens. Results RNA sequencing revealed that treatment with dihydrotestosterone (DHT) leads to subtle but significant changes in the expression of about 200 genes, encoding proteins of extracellular matrix or involved in signal transduction of growth factors (e.g., insulin/insulin growth factor 1). We showed that the most differentially expressed genes (DEGs), RGCC, RNF144B, NRCAM, TRIM22, FAM107A, IGFBP5, and LAMA2, are reproducibly regulated by different androgens in different genetic backgrounds. We showed, by overexpressing the androgen receptor in neuroblastoma cells SH-SY5Y or knocking it down in human neural stem cells, that this regulation involves the androgen receptor. A chromatin immunoprecipitation combined with direct sequencing analysis identified androgen receptor–bound sequences in nearly half of the DHT-DEGs and in numerous other genes. DHT-DEGs appear enriched in genes involved in ASD (ASXL3, NLGN4X, etc.), associated with ASD (NRCAM), or differentially expressed in patients with ASD (FAM107A, IGFBP5). Androgens increase human neural stem cell proliferation and survival in nutrient-deprived culture conditions, with no detectable effect on regulation of neurite outgrowth. Conclusions We characterized androgen action in neural progenitor cells, identifying DHT-DEGs that appear to be enriched in genes related to ASD. We also showed that androgens increase proliferation of neuronal precursors and protect them from death during their differentiation in nutrient-deprived conditions.

The SAGA coactivator complex and the nuclear pore–associated TREX-2 complex couple transcription with mRNA export. Evangelista et al. identify a novel interplay between TREX-2 and the deubiquitination module of SAGA that is necessary to maintain monoubiquitinated H2B levels required for efficient DNA repair through homologous recombination., DNA repair is critical to maintaining genome integrity, and its dysfunction can cause accumulation of unresolved damage that leads to genomic instability. The Spt–Ada–Gcn5 acetyltransferase (SAGA) coactivator complex and the nuclear pore–associated transcription and export complex 2 (TREX-2) couple transcription with mRNA export. In this study, we identify a novel interplay between human TREX-2 and the deubiquitination module (DUBm) of SAGA required for genome stability. We find that the scaffold subunit of TREX-2, GANP, positively regulates DNA repair through homologous recombination (HR). In contrast, DUBm adaptor subunits ENY2 and ATXNL3 are required to limit unscheduled HR. These opposite roles are achieved through monoubiquitinated histone H2B (H2Bub1). Interestingly, the activity of the DUBm of SAGA on H2Bub1 is dependent on the integrity of the TREX-2 complex. Thus, we describe the existence of a functional interaction between human TREX-2 and SAGA DUBm that is key to maintaining the H2B/HB2ub1 balance needed for efficient repair and HR.

International audience; The xeroderma pigmentosum group D (XPD) helicase is a subunit of transcription/DNA repair factor, transcription factor II H (TFIIH) that catalyzes the unwinding of a damaged DNA duplex during nucleotide excision repair. Apart from two canonical helicase domains, XPD is composed of a 4Fe-S cluster domain involved in DNA damage recognition and a module of uncharacterized function termed the “ARCH domain.” By investigating the consequences of a mutation found in a patient with trichothiodystrophy, we show that the ARCH domain is critical for the recruitment of the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex. Indeed, this mutation not only affects the interaction with the MAT1 CAK subunit, thereby decreasing the in vitro basal transcription activity of TFIIH itself and impeding the efficient recruitment of the transcription machinery on the promoter of an activated gene, but also impairs the DNA unwinding activity of XPD and the nucleotide excision repair activity of TFIIH. We further demonstrate the role of CAK in downregulating the XPD helicase activity within TFIIH. Taken together, our results identify the ARCH domain of XPD as a platform for the recruitment of CAK and as a potential molecular switch that might control TFIIH composition and play a key role in the conversion of TFIIH from a factor active in transcription to a factor involved in DNA repair.