RT Journal Article
SR Electronic
T1 ASH1L REGULATES THE STRUCTURAL DEVELOPMENT OF NEURONAL CIRCUITRY BY MODULATING BDNF/TrkB SIGNALING IN HUMAN NEURONS
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.18.954586
DO 10.1101/2020.02.18.954586
A1 Seon Hye Cheon
A1 Allison M. Culver
A1 Anna M. Bagnell
A1 Foster D. Ritchie
A1 Janay M. Clytus
A1 Mikayla McCord
A1 Carin M. Papendorp
A1 Evelyn Chukwurah
A1 Austin J. Smith
A1 Mara H. Cowen
A1 Pankaj S. Ghate
A1 Shannon W. Davis
A1 Judy S. Liu
A1 Sofia B. Lizarraga
YR 2020
UL http://biorxiv.org/content/early/2020/02/19/2020.02.18.954586.abstract
AB Autism spectrum disorders (ASD) are associated with defects in neuronal connectivity and are highly heritable. Genetic findings suggest that there is an overrepresentation of chromatin regulatory genes among the genes associated with ASD. ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for autism. ASH1L methylates Histone H3 on Lysine 36, which is proposed to result primarily in transcriptional activation. However, how mutations in ASH1L lead to deficits in neuronal connectivity associated with autism pathogenesis is not known. We report that ASH1L regulates neuronal morphogenesis by counteracting the catalytic activity of Polycomb Repressive complex 2 group (PRC2) in stem cell-derived human neurons. Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis. This is overcome by inhibition of PRC2 activity, indicating a balance between the Trithorax group protein ASH1L and PRC2 activity determines neuronal morphology and connectivity. Thus, ASH1L epigenetically regulates neuronal connectivity by modulating the BDNF-TrkB signaling pathway, which likely contributes to the neurodevelopmental pathogenesis associated with ASD in patients with ASH1L mutations.eTOC BLURB Cheon et al. report a novel epigenetic mechanism that implicates the counteracting activities of the evolutionarily conserved Trithorax (ASH1L) and Polycomb (PRC2) chromatin regulators, in the modulation of human neuronal connectivity by regulating the developmentally important TrkB-BDNF signaling pathway.HIGHLIGHTSASH1L regulates neuronal morphogenesis by modulating neurotrophin signalingCounteracting activities of Trithorax (ASH1L) and Polycomb (PRC2) affect neuronal arborizationLoss of ASH1L modulates growth cone size in human neurons