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Abstract
This study identifies KLF3 as a transcriptional regulator of muscle genes and reveals a novel synergistic interaction between KLF3 and serum response factor (SRF). Using quantitative proteomics, KLF3 was identified as one of several candidate factors that recognize the MPEX control element in the Muscle creatine kinase (MCK) promoter. Chromatin immunoprecipitation analysis indicated that KLF3 is enriched at many muscle gene promoters (MCK, Myosin heavy chain IIa, Six4, Calcium channel receptor α-1, and Skeletal α-actin), and two KLF3 isoforms are upregulated during muscle differentiation. KLF3 and SRF physically associate and synergize in transactivating the MCK promoter independently of SRF binding to CArG motifs. The zinc finger and repression domains of KLF3 plus the MADS box and transcription activation domain of SRF are implicated in this synergy. Our results provide the first evidence of a role for KLF3 in muscle gene regulation and reveal an alternate mechanism for transcriptional regulation by SRF via its recruitment to KLF binding sites. Since both factors are expressed in all muscle lineages, SRF may regulate many striated- and smooth-muscle genes that lack known SRF control elements, thus further expanding the breadth of the emerging CArGome.
We thank J. Angello, J. Buskin, D. Helterline, Q. Nguyen, P. Tai, and R. Welikson for technical assistance and/or critical discussions and P. Tai for artwork in . We are grateful to J. Klimek and D. Martin at the Institute for Systems Biology proteomics facility for help with mass spectrometry.
This work was supported by NIH-RO1-AR18860 (to S.D.H.); NIH-1P01-NS046788 (to S.D.H.); NIH-T32-HL007312, Experimental Pathology of Cardiovascular Disease (to C.L.H.); contract no. NO1-HV-28179 from the National Heart, Lung, and Blood Institute (to S.D.H. and C.L.H.); and grant no. P50GMO76547 from the National Institute of General Medical Sciences (to J.A.R.).