PUBLICATION
pH-controlled histone acetylation amplifies melanocyte differentiation downstream of MITF
- Authors
- Raja, D.A., Gotherwal, V., Burse, S.A., Subramaniam, Y.J., Sultan, F., Vats, A., Gautam, H., Sharma, B., Sharma, S., Singh, A., Sivasubbu, S., Gokhale, R.S., Natarajan, V.T.
- ID
- ZDB-PUB-191112-8
- Date
- 2019
- Source
- EMBO reports 21(1): e48333 (Journal)
- Registered Authors
- Sivasubbu, Sridhar
- Keywords
- epigenetics and zebrafish, histone acetylation, p300/CBP, pHÂ regulation, pigmentation
- MeSH Terms
-
- Acetylation
- Animals
- Cell Differentiation
- Epigenesis, Genetic
- Histones/genetics
- Histones/metabolism
- Hydrogen-Ion Concentration
- Melanocytes/metabolism
- Microphthalmia-Associated Transcription Factor*/genetics
- Microphthalmia-Associated Transcription Factor*/metabolism
- Pigmentation
- Zebrafish*/genetics
- Zebrafish*/metabolism
- PubMed
- 31709752 Full text @ EMBO Rep.
Citation
Raja, D.A., Gotherwal, V., Burse, S.A., Subramaniam, Y.J., Sultan, F., Vats, A., Gautam, H., Sharma, B., Sharma, S., Singh, A., Sivasubbu, S., Gokhale, R.S., Natarajan, V.T. (2019) pH-controlled histone acetylation amplifies melanocyte differentiation downstream of MITF. EMBO reports. 21(1):e48333.
Abstract
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 (CA14). Nuclear localization of CA14 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 CA14 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping