RT Journal Article
SR Electronic
T1 pH controlled histone acetylation amplifies melanocyte differentiation program downstream of MITF
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 545392
DO 10.1101/545392
A1 Desingu Ayyappa Raja
A1 Vishvabandhu Gotherwal
A1 Yogaspoorthi J Subramaniam
A1 Farina Sultan
A1 Archana Vats
A1 Archana Singh
A1 Sridhar Sivasubbu
A1 Rajesh S Gokhale
A1 Vivek T Natarajan
YR 2019
UL http://biorxiv.org/content/early/2019/02/08/545392.abstract
AB Tanning response and melanocyte differentiation are mediated by the central transcription factor MITF. Enigmatically, these involve rapid and selective induction of melanocyte maturation genes, while concomitantly maintaining the expression of other effectors. In this study using cell-based and zebrafish model systems, we elucidate a pH mediated feed-forward mechanism of epigenetic regulation that enables selective amplification of melanocyte maturation program. We demonstrate that MITF activation directly elevates the expression of Carbonic Anhydrase 14 (Ca14) enzyme. Nuclear localized Ca14 increases the intracellular pH, resulting in the activation of histone acetyl transferase activity of p300/CBP. In turn enhanced H3K27 histone acetylation marks of select differentiation genes facilitates their amplified expression by MITF. CRISPR-mediated targeted missense mutation of CA14 in zebrafish results in immature acidic melanocytes with decreased pigmentation, establishing the centrality of this mechanism in rapidly activating melanocyte differentiation. Thereby we reveal a novel epigenetic control through pH modulation that reinforces a deterministic cell fate by altering chromatin dynamics.