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bioRxiv · 10.1101/2024.05.19.593474

KAT3 mutations impair neural crest migration through EMT regulators snai1b and snai2 in Rubinstein Taybi Syndrome

Verma, S.·Dalabehera, S.·Gowda, S.·Chandrasekaran, K.·Singh, D.·Prasher, B.·Bapat, S.·Ramalingam, S.·Sachidanandan, C.
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Abstract

Rubinstein Taybi syndrome, a rare congenital disease is caused by mutation in KAT3 genes, EP300 and CREBBP. A subset of tissues affected in RSTS have their origin in neural crest cells, prompting our exploration into the role of KAT3 in neural crest development. Our zebrafish RSTS models generated by knocking down or mutating ep300a and cbpa genes, reveal defects in neural crest migration and its derived tissues when KAT3 genes are perturbed. We also demonstrate that the effects on neural crest can be reversed by HDAC inhibition in in morphant embryos. KAT3 knockdown causes downregulation of EMT regulators, snai1b and snai2. Snai2 is known to repress cdh6b in neural crest cells facilitating their delamination from neural tube and migration. We generated RSTS patient-derived iPSC line and differentiated them into neural crest cells in vitro. We show that role of KAT3 proteins in neural crest migration is conserved in human iPSC derived neural crest cells. Our findings make a case for classifying RSTS as a neurocristopathy. HighlightsO_LIPerturbation of KAT3 gene expression in zebrafish recapitulates the Rubinstein Taybi patient defects C_LIO_LIThe zebrafish model of Rubinstein Taybi model reveals defects in neural crest cell migration C_LIO_LIKAT3 proteins regulate snai2, snai1b and cdh6, genes important for neural crest migration C_LIO_LIThe neural crest migration defects in the zebrafish model can be partially rescued by modulating the global acetylation levels C_LIO_LIStudy of RSTS patient-derived neural crest cells reveals that the role of KAT3 in neural crest migration is conserved across vertebrates C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/593474v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1761fceorg.highwire.dtl.DTLVardef@220e21org.highwire.dtl.DTLVardef@1cdd311org.highwire.dtl.DTLVardef@1dc0e53_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Verma, S., Dalabehera, S., Gowda, S., Chandrasekaran, K., Singh, D., Prasher, B., Bapat, S., Ramalingam, S., Sachidanandan, C.. 2024-05-19. KAT3 mutations impair neural crest migration through EMT regulators snai1b and snai2 in Rubinstein Taybi Syndrome. https://doi.org/10.1101/2024.05.19.593474

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