MOZ directs the distal-less homeobox gene expression program during craniofacial development

Abstract

Oral clefts are common birth defects. Individuals with oral clefts who have identical genetic mutations regularly present with variable penetrance and severity. Epigenetic or chromatin-mediated mechanisms are commonly invoked to explain variable penetrance. However, specific examples of these are rare. Two functional copies of the MOZ (KAT6A, MYST3) gene, encoding a MYST family lysine acetyltransferase chromatin regulator, are essential for human craniofacial development, but the molecular role of MOZ in this context is unclear. Using genetic interaction and genomic studies, we have investigated the effects of loss of MOZ on the gene expression program during mouse development. Among the more than 500 genes differentially expressed after loss of MOZ, 19 genes had previously been associated with cleft palates. These included four distal-less homeobox (DLX) transcription factor-encoding genes, Dlx1, Dlx2, Dlx3 and Dlx5 and DLX target genes (including Barx1, Gbx2, Osr2 and Sim2). MOZ occupied the Dlx5 locus and was required for normal levels of histone H3 lysine 9 acetylation. MOZ affected Dlx gene expression cell-autonomously within neural crest cells. Our study identifies a specific program by which the chromatin modifier MOZ regulates craniofacial development.

KAT6A Acetylation of SMAD3 Regulates Myeloid‐Derived Suppressor Cell Recruitment, Metastasis, and Immunotherapy in Triple‐Negative Breast Cancer

“…KAT6A acetylation of the histone and nonhistone proteins plays a crucial role in regulating fundamental biological processes. KAT6A acetylated H3K23, H3K9, and H3K14 are important for tumorigenesis, [ 10 , 20 ] gene expression, [ 51 , 52 , 53 ] and immune responses. [ 11 ] Nonhistone protein p53 acetylated by KAT6A was identified in cell senescence.…”

High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour‐associated T lymphocyte infiltration

“…Conversely, these results also indicate that high WTAP expression may have an effect on tumour immunosuppression. DLX2, DLX5, SIX1, HOXB5, HOXC6, HOXC8, RBM48 and KRAS are genes involved in the regulation of mRNA expression and transcription. m6A is an important type of RNA modification.…”

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders

“…Both mouse models presented with cardiac defects, caused by Tbx1 repression in the absence of Kat6a (Voss et al, 2012). In addition, both early and late exon Kat6a knockouts exhibited a loss of hematopoietic stem cells, and craniofacial dysmorphisms, including cleft palates (Voss et al, 2012;Vanyai et al, 2019). Except for mild craniofacial dysmorphisms and heart defects, these mouse models do not appear to phenocopy the human condition.…”

“…Initially, Kat6a deficiency was examined in mutant zebrafish obtained through ENU mutagenesis, which resulted in aberrant craniofacial development (Miller et al, 2004;Crump, 2006). As mentioned above, Kat6a is a key player in the proper expression of the Hox genes that define segmental identity (Crump, 2006;Vanyai et al, 2019). In these Kat6a-deficient zebrafish, the second pharyngeal arch of the cranial neural crest was replaced by a duplicated jaw structure (Miller et al, 2004;Crump, 2006).…”