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pH‐controlled histone acetylation amplifies melanocyte differentiation downstream of MITF
Author(s) -
Raja Desingu Ayyappa,
Gotherwal Vishvabandhu,
Burse Shaunak A,
Subramaniam Yogaspoorthi J,
Sultan Farina,
Vats Archana,
Gautam Hemlata,
Sharma Babita,
Sharma Sachin,
Singh Archana,
Sivasubbu Sridhar,
Gokhale Rajesh S,
Natarajan Vivek T
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948333
Subject(s) - microphthalmia associated transcription factor , zebrafish , biology , melanocyte , microbiology and biotechnology , chromatin , transcription factor , histone , cellular differentiation , epigenetics , acetylation , regulation of gene expression , genetics , gene , melanoma
Tanning response and melanocyte differentiation are mediated by the central transcription factor MITF . This involves the rapid and selective induction of melanocyte maturation genes, while concomitantly the expression of other effector genes is maintained. In this study, using cell‐based and zebrafish model systems, we report on a pH ‐mediated feed‐forward mechanism of epigenetic regulation that enables selective amplification of the melanocyte maturation program. We demonstrate that MITF activation directly elevates the expression of the enzyme carbonic anhydrase 14 ( CA 14). Nuclear localization of CA 14 leads to an increase of the intracellular pH , resulting in the activation of the histone acetyl transferase p300/ CBP . In turn, enhanced H3K27 histone acetylation at selected differentiation genes facilitates their amplified expression via MITF . CRISPR ‐mediated targeted missense mutation of CA 14 in zebrafish results in the formation of immature acidic melanocytes with decreased pigmentation, establishing a central role for this mechanism during melanocyte differentiation in vivo . Thus, we describe an epigenetic control system via pH modulation that reinforces cell fate determination by altering chromatin dynamics.