MKL1/2 and ELK4 co-regulate distinct serum response factor (SRF) transcription programs in macrophages.
BACKGROUND
Serum response factor (SRF) is a widely expressed transcription factor involved in multiple regulatory programs. It is believed that SRF can toggle between disparate programs of gene expression through association with different cofactors. However, the direct evidence as to how these factors function on a genome-wide level is still lacking.


RESULTS
In the present study, I explored the functions of SRF and its representative cofactors, megakaryoblastic leukemia 1/2 (MKL1/2) and ETS-domain protein 4 (ELK4), during fungal infection challenge in macrophages. The knockdown study, combined with gene expression array analysis, revealed that MKL1/2 regulated SRF-dependent genes were related to actin cytoskeleton organization, while ELK4 regulated SRF-dependent genes were related to external stimulus responses. Subsequent chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) suggested that many of these regulations were mediated directly in cis.


CONCLUSIONS
I conclude that SRF utilizes MKL1/2 to fulfill steady state cellular functions, including cytoskeletal organization, and utilizes ELK4 to facilitate acute responses to external infection. Together, these findings indicate that SRF, along with its two cofactors, are important players in both cellular homeostasis and stress responses in macrophages.
Medical Systems Biology Research Center, Department of Biomedical Engineering, Tsinghua University School of Medicine, Beijing 100084, China. xielan@tsinghua.edu.cn.
Lan
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Xie
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D059372:Nucleotide Motifs; D056510:Position-Specific Scoring Matrices; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D015203:Reproducibility of Results; D026362:Serum Response Factor / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015054:Zymosan / Q000494:pharmacology; D050808:ets-Domain Protein Elk-4 / Q000235:genetics / Q000378:metabolism*
C494194:Elk4 protein, mouse; C511173:Mrtfa protein, mouse; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; C576273:myocardin-like protein 2, mouse; D050808:ets-Domain Protein Elk-4; D015054:Zymosan