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2015 ; 8
(ä): 45
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Tip60 complex binds to active Pol II promoters and a subset of enhancers and
co-regulates the c-Myc network in mouse embryonic stem cells
#MMPMID26550034
Ravens S
; Yu C
; Ye T
; Stierle M
; Tora L
Epigenetics Chromatin
2015[]; 8
(ä): 45
PMID26550034
show ga
BACKGROUND: Tip60 (KAT5) is the histone acetyltransferase (HAT) of the mammalian
Tip60/NuA4 complex. While Tip60 is important for early mouse development and
mouse embryonic stem cell (mESC) pluripotency, the function of Tip60 as reflected
in a genome-wide context is not yet well understood. RESULTS: Gel filtration of
nuclear mESCs extracts indicate incorporation of Tip60 into large molecular
complexes and exclude the existence of large quantities of "free" Tip60 within
the nuclei of ESCs. Thus, monitoring of Tip60 binding to the genome should
reflect the behaviour of Tip60-containing complexes. The genome-wide mapping of
Tip60 binding in mESCs by chromatin immunoprecipitation (ChIP) coupled with
high-throughput sequencing (ChIP-seq) shows that the Tip60 complex is present at
promoter regions of predominantly active genes that are bound by RNA polymerase
II (Pol II) and contain the H3K4me3 histone mark. The coactivator HAT complexes,
Tip60- and Mof (KAT8)-containing (NSL and MSL), show a global overlap at
promoters, whereas distinct binding profiles at enhancers suggest different
regulatory functions of each essential HAT complex. Interestingly, Tip60
enrichment peaks at about 200 bp downstream of the transcription start sites
suggesting a function for the Tip60 complexes in addition to histone acetylation.
The comparison of genome-wide binding profiles of Tip60 and c-Myc, a somatic cell
reprogramming factor that binds predominantly to active genes in mESCs,
demonstrate that Tip60 and c-Myc co-bind at 50-60 % of their binding sites. We
also show that the Tip60 complex binds to a subset of bivalent developmental
genes and defines a set of mESC-specific enhancer as well as super-enhancer
regions. CONCLUSIONS: Our study suggests that the Tip60 complex functions as a
global transcriptional co-activator at most active Pol II promoters, co-regulates
the ESC-specific c-Myc network, important for ESC self-renewal and cell
metabolism and acts at a subset of active distal regulatory elements, or super
enhancers, in mESCs.