Transcriptional regulation plays essential roles in tissue-specific gene expression for proper embryonic development and mature organ function.  Transcription factors form multi-protein complexes, and such complexes, not individual transcription factors, dictate the specificity of downstream gene expression.  Despite recent progress of transcription factor research, little is known about combinatorial actions of DNA-binding transcription factors, co-factors and histone modifying enzymes.  It is therefore important to elucidate and characterize novel transcriptional factor complexes that are important for development and disease.  In addition, since transcription factors act as "molecular switches" for downstream target genes, it is critical to analyze the functions of target genes that directly regulate cellular functions downstream of transcriptional control.  Characterization of those genes may provide a link from basic studies of transcriptional mechanisms to the etiologies of human diseases.  Using biochemical approaches and mouse model analyses, we are pursuing these two general paradigms, characterization of novel transcriptional factor complexes and downstream target genes, mainly focusing on the cardiovascular system and skeletal muscle.

1) Transcriptional factor complexes implicated in cardiovascular development and disease

King IN, Kathiriya IS, Murakami M, Nakagawa M, Gardner KA, Srivastava D, Nakagawa O.  Hrt and Hes negatively regulate Notch signaling through interactions with RBP-Jkappa.  Biochem. Biophys. Res. Commun.  345(1):446-452, 2006.

Murakami M, Nakagawa M, Olson EN, Nakagawa O.  A WW domain protein TAZ is a critical co-activator for TBX5, a transcription factor implicated in Holt-Oram syndrome.  Proc. Nat. Acad. Sci. USA  102(50): 18034-18039, 2005.

Kathiriya IS, King IN, Murakami M, Nakagawa M, Astle JA, Gardner KA, Gerard RD, Olson EN, Srivastava D, Nakagawa O. Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism.
J. Biol. Chem.  279(52): 54937-54943, 2004.

Yamagishi H, Yamagishi C, Nakagawa O, Harvey RP, Olson EN, Srivastava D.  The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricular formation.  Dev. Biol.  239(2): 190-203, 2001.

Nakagawa O, McFadden DG, Nakagawa M, Yanagisawa H, Hu T, Srivastava D, Olson EN.  Members of the HRT family of bHLH proteins act as transcriptional repressors downstream of Notch signaling.  Proc. Nat. Acad. Sci. USA  97(25): 13655-13660, 2000.

Nakagawa O, Nakagawa M, Richardson JA, Olson EN, Srivastava D.  HRT1, HRT2, HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic and pharyngeal arch segments.  Dev. Biol.  216(1): 72-84, 1999.

2) Downstream target genes of cardiac- and muscle-specific transcription factors

Nakagawa O, Arnold M, Nakagawa M, Hamada H, Shelton JM, Kusano H, Harris TM, Childs G, Campbell KP, Richardson JA, Nishino I, Olson EN.  Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2.  Genes Dev.  19(17): 2066-2077, 2005.

Phan D, Rasmussen TL, Nakagawa O, McAnally J, Gottlieb PD, Tucker PW, Richardson JA, Bassel-Duby R, Olson EN.  Bop, a regulator of right ventricular heart development, is a direct transcriptional target of MEF2C in the anterior heart field.  Development  132(11): 2669-2678, 2005.

Gottlieb PD, Pierce SA, Sims RJ III, Yamagishi H, Weihe EK, Harriss JV, Maika SD, Kuziel WA, King HL, Olson EN, Nakagawa O, Srivastava D.  Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis.  Nature Genet.  31(1): 25-32, 2002.

Liu Z-P, Nakagawa O, Nakagawa M, Yanagisawa H, Passier R, Richardson JA, Srivastava D, Olson EN.
CHAMP, a novel cardiac-specific helicase regulated by MEF2C.  Dev. Biol.  234(2): 497-509, 2001.