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A dual role for Nucleolin identified by systems analysis of cardiac chromatin remodelers
Author(s) -
Monte Emma,
Mouillesseaux Kevin,
Chen Haodong,
Ren Shuxun,
Wang Yibin,
Chen JauNian,
Vondriska Thomas M,
Franklin Sarah
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.1213.1
Subject(s) - nucleolin , biology , zebrafish , myocyte , microbiology and biotechnology , chromatin , heart development , muscle hypertrophy , medicine , endocrinology , embryonic stem cell , genetics , nucleolus , dna , cytoplasm , gene
To elucidate mechanisms of chromatin reprogramming during cardiac development and disease, we used a systems approach to identify, screen, and validate changes to the nuclear proteome. Quantitative proteomic analysis of chromatin fractions from mouse hearts in basal, hypertrophy or failing conditions identified 338 proteins whose abundances change. One candidate was Nucleolin (Ncl), which increases 3‐fold in hypertrophy. Using a functional screen in zebrafish embryos, we characterized a novel role for Ncl to affect cardiac looping and differentiation. 48‐hour embryos express Ncl in the heart, with in situ hybridization demonstrating BMP4 restricted to the atrial/ventricular boundary. After Morpholino knockdown (KD) of Ncl, BMP4 is found throughout the ventricle, suggesting delayed myocyte differentiation. This is accompanied by defects in chamber looping, with 20% of fish failing to loop or reverse looping, a phenotype seen in 29% of fish after over expression; no changes in myocyte size were observed in KD fish. Delayed hearts exhibit a decreased heart rate and increased fractional shortening. Finally, in isolated rat myocytes, loss of Ncl alters transcription of SERCA , ANF , and β‐MHC , whose expression changes are hallmarks of cardiac hypertrophy. This suggests that changes in Ncl levels affect differentiation during development, whereas in disease it may drive the hypertrophic response. NIH funded.