Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function.

[wolf-hirschhorn syndrome]

The NSD (nuclear receptor-binding SET domain protein ) family encodes methyltransferases that are important in multiple aspects of development and disease . Perturbations in NSD family members can lead to Sotos syndrome and Wolf-Hirschhorn syndrome as well as cancers such as acute myeloid leukemia . Previous studies have implicated NSD 1 (KMT 3 B ) in transcription and methylation of histone H 3 at lysine 36 (H 3 -K 36 ), but its molecular mechanism in these processes remains largely unknown . Here we describe an NSD 1 regulatory network in human cells . We show that NSD 1 binds near various promoter elements and regulates multiple genes that appear to have a concerted role in various processes , such as cell growth /cancer , keratin biology , and bone morphogenesis . In particular , we show that NSD 1 binding is concentrated upstream of gene targets such as the bone morphogenetic protein 4 (BMP 4 ) and zinc finger protein 3 6 C 3 H type -like 1 (ZFP 36 L 1 /TPP ). NSD 1 regulates the levels of the various forms of methylation at H 3 -K 36 primarily , but not exclusively , within the promoter proximal region occupied by NSD 1 . At BMP 4 we find that this reduces the levels of RNAP II recruited to the promoter , suggesting a role for NSD 1 -dependent methylation in initiation . Interestingly , we also observe that the RNAP II molecules that lie within BMP 4 have inappropriate persistence of serine-5 phosphorylation and reduced levels of serine-2 phosphorylation within the C-terminal domain (CTD ) of the large subunit of RNAP II . Our findings indicate that NSD 1 regulates RNAP II recruitment to BMP 4 , and failure to do so leads to reduced gene expression and abrogated levels of H 3 K 36 Me and CTD phosphorylation .

Diseases
Validation

Diseases presenting "multiple genes" symptom

22q11.2 deletion syndrome

congenital toxoplasmosis

cowden syndrome

oculocutaneous albinism

wolf-hirschhorn syndrome

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