Corepressor N-CoR (nuclear receptor corepressor) and the highly related protein SMRT (silencing mediator of retinoid and thyroid hormone receptor) play important roles in different biological processes including proliferation, differentiation, and development. Understanding the biological function of these corepressors requires identification and characterization of their interacting proteins. Here we report the characterization of a novel N-CoR-interacting protein, JMJD2A (previously known as KIAA0677). JMJD2A is an evolutionarily conserved nuclear protein containing many functionally unknown domains. In eukaryotic cells, DNA is wrapped around histone octamers that consist of two molecules of each of the core histones H2A, H2B, H3, and H4 to form chromatin. Although chromatin was once considered to serve only as a structural component for the storage of genomic information, it is now widely accepted that chromatin also plays essential roles in the regulation of multiple processes including DNA replication, transcription, and repair (2,8,47,49). Numerous proteins and protein complexes regulate transcription by posttranslationally modifying histones. These modifications include acetylation, methylation, phosphorylation, ubiquitylation, and sumoylation (2, 39, 54). It is well established that increased histone acetylation generally correlates with transcription activation and that deacetylation correlates with repression. Although the precise mechanism that links acetylation to transcriptional regulation is still not fully understood, histone acetylation catalyzed by histone acetyltransferases are thought to weaken DNA/histone interactions and affect higher-order chromatin folding to modulate the accessibility of promoter sequences to transcription factors and basal transcriptional machinery (12,36). In addition, histone acetylation can serve as a specific code for binding of transcriptional regulatory proteins (40,42). On the other hand, histone deacetylation catalyzed by HDACs (histone deacetylases) antagonizes acetyltransferase activity and favors the tight compaction of the histone-DNA complex.Numerous HDAC-containing repression complexes have been identified (3,4,9,11,48). Among them are N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone receptor) complexes. SMRT and N-CoR are two highly related proteins originally isolated and characterized by their ability to interact with the unliganded forms of nuclear hormone receptors and confer transcriptional repression (18,34,35). Recent studies have implicated N-CoR and SMRT in repression by diverse transcription factors including Mad/Mxi, BCL6/LAZ3, ETO, CBF, and REST/ NRSF (7,11,22,23,32,33,43,44). Mouse N-CoR is required for early embryonic development, and N-CoR null mice show defects in neural cell differentiation and developmental progression of specific erythrocytes and thymocytes (17,21). To understand the mechanism by which SMRT and N-CoR mediate transcriptional repression, several groups have attempted isolat...
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