TY - JOUR
T1 - Differential usage of transcriptional repressor Zeb2 enhancers distinguishes adult and embryonic hematopoiesis
AU - Huang, Xiao
AU - Ferris, Stephen T.
AU - Kim, Sunkyung
AU - Choudhary, Mayank N.K.
AU - Belk, Julia A.
AU - Fan, Changxu
AU - Qi, Yanyan
AU - Sudan, Raki
AU - Xia, Yu
AU - Desai, Pritesh
AU - Chen, Jing
AU - Ly, Nghi
AU - Shi, Quanming
AU - Bagadia, Prachi
AU - Liu, Tiantian
AU - Guilliams, Martin
AU - Egawa, Takeshi
AU - Colonna, Marco
AU - Diamond, Michael S.
AU - Murphy, Theresa L.
AU - Satpathy, Ansuman T.
AU - Wang, Ting
AU - Murphy, Kenneth M.
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/7/13
Y1 - 2021/7/13
N2 - The transcriptional repressor ZEB2 regulates development of many cell fates among somatic, neural, and hematopoietic lineages, but the basis for its requirement in these diverse lineages is unclear. Here, we identified a 400-basepair (bp) region located 165 kilobases (kb) upstream of the Zeb2 transcriptional start site (TSS) that binds the E proteins at several E-box motifs and was active in hematopoietic lineages. Germline deletion of this 400-bp region (Zeb2Δ−165mice) specifically prevented Zeb2 expression in hematopoietic stem cell (HSC)-derived lineages. Zeb2Δ−165 mice lacked development of plasmacytoid dendritic cells (pDCs), monocytes, and B cells. All macrophages in Zeb2Δ−165 mice were exclusively of embryonic origin. Using single-cell chromatin profiling, we identified a second Zeb2 enhancer located at +164-kb that was selectively active in embryonically derived lineages, but not HSC-derived ones. Thus, Zeb2 expression in adult, but not embryonic, hematopoiesis is selectively controlled by the –165-kb Zeb2 enhancer.
AB - The transcriptional repressor ZEB2 regulates development of many cell fates among somatic, neural, and hematopoietic lineages, but the basis for its requirement in these diverse lineages is unclear. Here, we identified a 400-basepair (bp) region located 165 kilobases (kb) upstream of the Zeb2 transcriptional start site (TSS) that binds the E proteins at several E-box motifs and was active in hematopoietic lineages. Germline deletion of this 400-bp region (Zeb2Δ−165mice) specifically prevented Zeb2 expression in hematopoietic stem cell (HSC)-derived lineages. Zeb2Δ−165 mice lacked development of plasmacytoid dendritic cells (pDCs), monocytes, and B cells. All macrophages in Zeb2Δ−165 mice were exclusively of embryonic origin. Using single-cell chromatin profiling, we identified a second Zeb2 enhancer located at +164-kb that was selectively active in embryonically derived lineages, but not HSC-derived ones. Thus, Zeb2 expression in adult, but not embryonic, hematopoiesis is selectively controlled by the –165-kb Zeb2 enhancer.
KW - Zeb2
KW - chromatin structure
KW - enhancer
KW - hematopoiesis
KW - transcriptional regulation
KW - zinc finger E-box binding homeobox 2
UR - http://www.scopus.com/inward/record.url?scp=85107277206&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2021.04.015
DO - 10.1016/j.immuni.2021.04.015
M3 - Article
C2 - 34004142
AN - SCOPUS:85107277206
SN - 1074-7613
VL - 54
SP - 1417-1432.e7
JO - Immunity
JF - Immunity
IS - 7
ER -