pH controlled histone acetylation amplifies melanocyte differentiation program downstream of MITF

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.