Choi, Si Ho and Gearhart, Micah and Cui, Ziyou and Bosnakovski, Darko and Kim, Minjee and Schennum, Natalie and Kyba, Michael (2016) DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. Nucleic Acids Research.
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Abstract
Ectopic expression of the double homeodomain transcription
factor DUX4 causes facioscapulohumeral
muscular dystrophy (FSHD). Mechanisms of action
of DUX4 are currently unknown. Using immortalized
human myoblasts with a titratable DUX4 transgene,
we identify by mass spectrometry an interaction between
the DUX4 C-terminus and the histone acetyltransferases
p300/CBP. Chromatin immunoprecipitation
shows that DUX4 recruits p300 to its target
gene, ZSCAN4, displaces histone H3 from the
center of its binding site, and induces H3K27Ac in
its vicinity, but C-terminal deleted DUX4 does not.
We show that a DUX4 minigene, bearing only the
homeodomains and C-terminus, is transcriptionally
functional and cytotoxic, and that overexpression
of a nuclear targeted C-terminus impairs the ability
of WT DUX4 to interact with p300 and to regulate
target genes. Genomic profiling of DUX4, histone
H3, and H3 modifications reveals that DUX4 binds
two classes of loci: DNase accessible H3K27Acrich
chromatin and inaccessible H3K27Ac-depleted
MaLR-enriched chromatin. At this latter class, it acts
as a pioneer factor, recruiting H3K27 acetyltransferase
activity and opening the locus for transcription.
In concert with local increased H3K27Ac, the
strong H3K27Ac peaks at distant sites are significantly
depleted of H3K27Ac, thus DUX4 uses its Cterminus
to induce a global reorganization of H3K27
acetylation.
| Item Type: | Article |
|---|---|
| Subjects: | Medical and Health Sciences > Basic medicine |
| Divisions: | Faculty of Medical Science |
| Depositing User: | Darko Bosnakovski |
| Date Deposited: | 07 Feb 2018 08:54 |
| Last Modified: | 07 Feb 2018 08:54 |
| URI: | https://eprints.ugd.edu.mk/id/eprint/19347 |
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