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|Title:||Identification of a novel enhancer of CEBPE essential for granulocytic differentiation.||Authors:||Shyamsunder, Pavithra
Teoh, Weoi Woon
Lim, Mei Chee
Hossain, Md Zakir
Koeffler, H Phillip
|Issue Date:||5-Apr-2019||Publisher:||American Society of Hematology||Citation:||Shyamsunder, Pavithra, Shanmugasundaram, Mahalakshmi, Mayakonda, Anand, Dakle, Pushkar, Teoh, Weoi Woon, Han, Lin, Kanojia, Deepika, Lim, Mei Chee, Fullwood, Melissa, An, Omer, Yang, Henry, Jizhong, Shi, Hossain, Md Zakir, Madan, Vikas, Koeffler, H Phillip (2019-04-05). Identification of a novel enhancer of CEBPE essential for granulocytic differentiation.. Blood 133 (23) : 2507-2517. ScholarBank@NUS Repository. https://doi.org/10.1182/blood.2018886077||Abstract:||CCAAT/enhancer binding protein epsilon (CEBPE) is an essential transcription factor for granulocytic differentiation. Mutations of CEBPE occur in individuals with neutrophil-specific granule deficiency (SGD), which is characterized by defects in neutrophil maturation. Cebpe knockout mice also exhibit defects in terminal differentiation of granulocytes, a phenotype reminiscent of SGD. Analysis of DNase-Seq data revealed an open chromatin region 6kb downstream of the transcriptional start site of Cebpe in murine myeloid cells. We identified interaction between this +6 kb region and the core promoter of Cebpe using 4C-seq. To understand the role of this putative enhancer in transcriptional regulation of Cebpe, we targeted it using dCas9-KRAB and observed a significant downregulation of transcript and protein levels of CEBPE in cells expressing guide RNA targeting the +6 kb region. To investigate further the role of this novel enhancer in myelopoiesis, we generated mice with deletion of this region using CRISPR/Cas9 technology. Germline deletion of the +6 kb enhancer resulted in reduced levels of CEBPE and its target genes and caused a severe block in granulocytic differentiation. We also identified binding of CEBPA and CEBPE to the +6 kb enhancer which suggests their role in regulating the expression of Cebpe. In summary, we have identified a novel enhancer crucial for regulating expression of Cebpe, and required for normal granulocytic differentiation.||Source Title:||Blood||URI:||https://scholarbank.nus.edu.sg/handle/10635/155163||ISSN:||0006-4971
|Appears in Collections:||Staff Publications|
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