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Title: Identification of a novel enhancer of CEBPE essential for granulocytic differentiation.
Authors: 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 
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.
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
ISSN: 0006-4971
DOI: 10.1182/blood.2018886077
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