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Articles by Mitchell A. Lazar
Total Records ( 2 ) for Mitchell A. Lazar
  Jing Wang and Mitchell A. Lazar
  The nuclear receptor Rev-erbα is a potent transcriptional repressor that regulates circadian rhythm and metabolism. Here we demonstrate a dissociation between Rev-erbα mRNA and protein levels that profoundly influences adipocyte differentiation. During adipogenesis, Rev-erbα gene expression initially declines and subsequently increases. Remarkably, Rev-erbα protein levels are nearly the opposite, increasing early in adipogenesis and then markedly decreasing in adipocytes. The Rev-erbα protein is necessary for the early mitotic events that are required for adipogenesis. The subsequent reduction in Rev-erbα protein, due to increased degradation via the 26S proteasome, is also required for adipocyte differentiation because Rev-erbα represses the expression of PPARγ2, the master transcriptional regulator of adipogenesis. Thus, opposite to what might be predicted from Rev-erbα gene expression, Rev-erbα protein levels must rise and then fall for adipocyte differentiation to occur.
  David J. Steger , Martina I. Lefterova , Lei Ying , Aaron J. Stonestrom , Michael Schupp , David Zhuo , Adam L. Vakoc , Ja- Eun Kim , Junjie Chen , Mitchell A. Lazar , Gerd A. Blobel and Christopher R. Vakoc
  The histone H3 lysine 79 methyltransferase DOT1L/KMT4 can promote an oncogenic pattern of gene expression through binding with several MLL fusion partners found in acute leukemia. However, the normal function of DOT1L in mammalian gene regulation is poorly understood. Here we report that DOT1L recruitment is ubiquitously coupled with active transcription in diverse mammalian cell types. DOT1L preferentially occupies the proximal transcribed region of active genes, correlating with enrichment of H3K79 di- and trimethylation. Furthermore, Dot1l mutant fibroblasts lacked H3K79 di- and trimethylation at all sites examined, indicating that DOT1L is the sole enzyme responsible for these marks. Importantly, we identified chromatin immunoprecipitation (ChIP) assay conditions necessary for reliable H3K79 methylation detection. ChIP-chip tiling arrays revealed that levels of all degrees of genic H3K79 methylation correlate with mRNA abundance and dynamically respond to changes in gene activity. Conversion of H3K79 monomethylation into di- and trimethylation correlated with the transition from low- to high-level gene transcription. We also observed enrichment of H3K79 monomethylation at intergenic regions occupied by DNA-binding transcriptional activators. Our findings highlight several similarities between the patterning of H3K4 methylation and that of H3K79 methylation in mammalian chromatin, suggesting a widespread mechanism for parallel or sequential recruitment of DOT1L and MLL to genes in their normal "on" state.
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