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WDR5, ASH2L, and RBBP5 control the efficiency of FOS transcript processing

Abstract

H3K4 trimethylation is strongly associated with active transcription. The deposition of this mark is catalyzed by SET-domain methyltransferases, which consist of a subcomplex containing WDR5, ASH2L, and RBBP5 (the WAR subcomplex); a catalytic SET-domain protein; and additional complexspecific subunits. The ERK MAPK pathway also plays an important role in gene regulation via phosphorylation of transcription factors, co-regulators, or histone modifier complexes. However, the potential interactions between these two pathways remain largely unexplored. We investigated their potential interplay in terms of the regulation of the immediate early gene (IEG) regulatory network. We found that depletion of components of the WAR subcomplex led to increased levels of unspliced transcripts of IEGs that did not necessarily reflect changes in their mature transcripts. This occurs in a manner independent from changes in the H3K4me3 levels at the promoter region. We focused on FOS and found that the depletion of WAR subcomplex components affected the efficiency of FOS transcript processing. Our findings show a new aspect of WAR subcomplex function in coordinating active transcription with efficient pre-mRNA processing.

Abbreviations

ChIP:

chromatin immunoprecipitation

EGF:

epidermal growth factor

ERK:

extracellular signal-regulated kinases

FBS:

fetal bovine serum

H3K4:

histone 3 lysine 4

H3K4me3:

trimethylation of histone 3 lysine 4

HAT:

histone acetyltransferase

HDAC:

histone deacetylase

HMT:

histone methyltransferases

IEG:

immediate early genes

MAPK:

mitogen-activated protein kinase

MLL:

mixed-lineage leukemia

NRO:

nuclear run on

PAGE:

polyacrylamide gel electrophoresis

PBS:

phosphate-buffered saline

Pol II:

RNA polymerase II

SDS:

sodium dodecyl sulphate

RNAi:

RNA interference

siRNA:

small interfering RNA

WAR:

WDR5-ASH2L-RBBP5

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Correspondence to Peik Lin Teoh.

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Teoh, P.L., Sharrocks, A.D. WDR5, ASH2L, and RBBP5 control the efficiency of FOS transcript processing. Cell Mol Biol Lett 19, 215–232 (2014). https://doi.org/10.2478/s11658-014-0190-8

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Keywords

  • RBBP5
  • ASH2L
  • WDR5
  • Histone methyltransferase
  • Immediate early gene
  • Splicing