TY - JOUR
T1 - In β-actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects
AU - Almuzzaini, Bader
AU - Sarshad, Aishe A.
AU - Rahmanto, Aldwin S.
AU - Hansson, Magnus L.
AU - Von Euler, Anne
AU - Sangfelt, Olle
AU - Visa, Neus
AU - Farrants, Ann Kristin Östlund
AU - Percipalle, Piergiorgio
N1 - Funding Information:
The authors thank C. Ampe (University of Ghent, Ghent, Belgium) and R. Treissman (London Research Institute, London, United Kingdom) for kindly providing the β-actin+/+ MEFs, β-actin-/- MEFs, and β-actin constructs. The authors also thank M. Corcoran and M. Rahman (both from the Karolinska Institute) for technical help. This work was supported by grants from the Swedish Research Council and the Swedish Cancer Society to P.P., O.S., and N.V. B.A.M. was cofunded by National Guard Health Affairs-King Abdullah International Medical Research Center, and A.A.S. was cofunded by a Karolinska Institute doctoral fellowship. M.H. was supported by a postdoctoral fellowship from the Swedish Society for Medical Research. A.S.R. was supported by funds from Radiumhemmets Forskningsfonder.
Publisher Copyright:
© 2016 FASEB.
PY - 2016/8
Y1 - 2016/8
N2 - Actin and nuclear myosin 1 (NM1) are regulators of transcription and chromatin organization. Using a genome-wide approach, we report here that β-actin binds intergenic and genic regions across the mammalian genome, associated with both protein-coding and rRNA genes. Within the rDNA, the distribution of β-actin correlated with NM1 and the other subunits of the B-WICH complex, WSTF and SNF2h. In β-actin-/- mouse embryonic fibroblasts (MEFs), we found that rRNA synthesis levels decreased concomitantly with drops in RNA polymerase I (Pol I) and NM1 occupancies across the rRNA gene. Reintroduction of wild-type β-actin, in contrast to mutated forms with polymerization defects, efficiently rescued rRNA synthesis underscoring the direct role for a polymerization-competent formofβ-actin in Pol I transcription. The rRNA synthesis defects intheβ-actin-/- MEFs are a consequence of epigenetic reprogramming with up-regulation of the repressive mark H3K4me1 (monomethylation of lys4 on histone H3) and enhanced chromatin compaction at promoter-proximal enhancer (T0 sequence), which disturb binding of the transcription factor TTF1. Wepropose a novel genome-wide mechanism where the polymerase-associated β-actin synergizes with NM1 to coordinate permissive chromatin with Pol I transcription, cell growth, and proliferation.
AB - Actin and nuclear myosin 1 (NM1) are regulators of transcription and chromatin organization. Using a genome-wide approach, we report here that β-actin binds intergenic and genic regions across the mammalian genome, associated with both protein-coding and rRNA genes. Within the rDNA, the distribution of β-actin correlated with NM1 and the other subunits of the B-WICH complex, WSTF and SNF2h. In β-actin-/- mouse embryonic fibroblasts (MEFs), we found that rRNA synthesis levels decreased concomitantly with drops in RNA polymerase I (Pol I) and NM1 occupancies across the rRNA gene. Reintroduction of wild-type β-actin, in contrast to mutated forms with polymerization defects, efficiently rescued rRNA synthesis underscoring the direct role for a polymerization-competent formofβ-actin in Pol I transcription. The rRNA synthesis defects intheβ-actin-/- MEFs are a consequence of epigenetic reprogramming with up-regulation of the repressive mark H3K4me1 (monomethylation of lys4 on histone H3) and enhanced chromatin compaction at promoter-proximal enhancer (T0 sequence), which disturb binding of the transcription factor TTF1. Wepropose a novel genome-wide mechanism where the polymerase-associated β-actin synergizes with NM1 to coordinate permissive chromatin with Pol I transcription, cell growth, and proliferation.
KW - Genome-wide analysis
KW - NM1
KW - Nuclear actin
KW - RRNA synthesis
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U2 - 10.1096/fj.201600280R
DO - 10.1096/fj.201600280R
M3 - Article
C2 - 27127100
AN - SCOPUS:84982710701
SN - 0892-6638
VL - 30
SP - 2860
EP - 2873
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -