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Muscle Ring Finger 1 (MuRF1) and MuRF2 Regulate Gene Expression Mediated by the E2F Transcription Factors and are Necessary but Functionally Redundant During Developmental Cardiac Growth In Vivo
Author(s) -
Willis Monte S,
Wadosky Kristine M.,
Patterson Cam
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1085.10
Subject(s) - biology , e2f , transcription factor , gene , e2f1 , microbiology and biotechnology , genetics
We recently reported MuRF1 and MuRF2 are functionally redundant during cardiac development. Specifically, mice missing all four MuRF1 and MuRF2 alleles [MuRF1/MuRF2 double null (DN)] were born with a massive spontaneous hypertrophic cardiomyopathy and heart failure; mice that were null for one of the genes, but heterozygous for the other (i.e. MuRF1−/− //MuRF2+/− or MuRF1+/−//MuRF2−/−) were phenotypically identical to wild type mice. Microarray analysis of genes differentially expressed between MuRF1/MuRF2 DN, mice missing 3 of the four alleles, and wild type mice revealed a significant enrichment of genes regulated by the E2F transcription factor family. Over 85% of the differentially expressed genes had E2F promoter regions (E2f:DP; p<0.001). Western analysis of E2F revealed no differences between MuRF1/MuRF2 DN hearts and wild type hearts; however, chromatin IP studies revealed that MuRF1/MuRF2 DN hearts had significantly less binding of E2F1 in the promoter regions of genes previously defined to be regulated by E2F1 (p21, Brip1, and PDK4, p<0.01). These studies suggest that MuRF1 and MuRF2 play a redundant role in regulating developmental physiologic hypertrophy, by regulating E2F transcription factors essential for normal cardiac development by supporting E2F localization to the nucleus, but not through a process that degrades the transcription factor.