Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice
Details
Publication Year 2011-09, Volume 121, Issue #9, Page 3479-3491
Journal Title
JOURNAL OF CLINICAL INVESTIGATION
Publication Type
Journal Article
Abstract
Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Keywords
ACTIVATED PROTEIN-KINASE; ACUTE MYELOID-LEUKEMIA; ZINC-FINGER PROTEIN; STEM-CELLS; CBP GENES; MORF; MOZ; ACETYLATION; MUTATIONS; PATHWAYS
Publisher's Version
https://doi.org/10.1172/JCI43428
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2011-09-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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