ASH1L mediated transcription networks in autism spectrum disorders

项目总结

Project Summary Autism spectrum disorder (ASD) research has led to the discovery of highly penetrant mutations in chromatin modifiers and transcription factors. However, given the large number of ASD risk factors, a major challenge for ASD research is to establish convergent mechanisms that group apparently distinct genetic etiologies. We identified a novel point of convergence between the histone-methyltransferase ASH1L, a major ASD genetic risk factor, and a cluster of ASD high-risk genes (e.g. FOXP1, RIMS1, NRX1α). Transcriptional programs modulated by ASH1L that lead to neuronal dysfunction are poorly understood. Our studies uncover a transcriptional and epigenetic node linked to cell and circuit dysfunction underlying ASD phenotypes. Our central hypothesis is that ASH1L counteracts Polycomb (PRC2) activity to orchestrate neuronal development by modulating transcriptional programs governing synaptic function and neuronal morphogenesis. We have observed that ASH1L-deficient neurons show significantly decreased levels of FOXP1 expression, indicating transcriptional control of FOXP1 by ASH1L. It is therefore possible that this relationship underlies overlapping features in the changes in brain structure and their associated transcriptional networks caused by FOXP1 and ASH1L deficiency. In this Supplement, we will test the hypothesis that ASH1L regulates transcriptional programs mediated by its downstream target, FOXP1, via inhibition of PRC2 activity. We will determine how FOXP1 contributes to the ASH1L mutant phenotype in two Aims. In Aim 1, we will identify convergent and divergent mechanisms by characterizing the morphological and anatomical phenotypes of ASH1L and FOXP1 mutant mouse brains. In Aim 2, we will define the relationship between ASH1L and FOXP1 neuronal transcriptional networks, including the involvement of PRC2, by performing transcriptomic analysis of ASH1L and FOXP1-deficient mouse brains. These Aims will not only provide clearer insight into our studies of ASH1L-mediated mechanisms of neuronal development, but also constitute the research training component of this Diversity Supplement for our post-baccalaureate research assistant. Funds from the Supplement will allow our research assistant to integrate into our ASH1L research team while gaining bench experience in histological techniques and advanced microscopy, molecular expression analysis and bioinformatics. Along with conference activities and exposure to rigor, ethics, scientific communication and elements of translational research, our assistant will receive career development training and guidance in preparation for admission to a strong MD/PhD program in neuroscience research.