제1저자 김태균(환경의생물학교실, 의과학과 졸업 Phy-Sci) 김수은(환경의생물학교실)
교신저자 김형표(환경의생물학교실, BK21)
Exp Mol Med. 2017 Aug 25(8):e371. doi: 10.1038/emm.2017.124.
CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice.
Kim TG1,2,3, Kim S1,2, Jung S1, Kim M1, Yang B1,2, Lee MG2,3, Kim HP1,2.
1Department of Environmental Medical Biology, Institute. of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea.2BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.3Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
Hematopoiesis involves a series of lineage differentiation programs initiated in hematopoietic stem cells (HSCs) found in bone marrow (BM). To ensure lifelong hematopoiesis, various molecular mechanisms are needed to maintain the HSC pool. CCCTC-binding factor (CTCF) is a DNA-binding, zinc-finger protein that regulates the expression of its target gene by organizing higher order chromatin structures. Currently, the role of CTCF in controlling HSC homeostasis is unknown. Using a tamoxifen-inducible CTCF conditional knockout mouse system, we aimed to determine whether CTCF regulates the homeostatic maintenance of HSCs. In adult mice, acute systemic CTCF ablation led to severe BM failure and the rapid shrinkage of multiple c-Kithi progenitor populations, including Sca-1+ HSCs. Similarly, hematopoietic system-confined CTCF depletion caused an acute loss of HSCs and highly increased mortality. Mixed BM chimeras reconstituted with supporting BM demonstrated that CTCF deficiency-mediated HSC depletion has both cell-extrinsic and cell-intrinsic effects. Although c-Kithi myeloid progenitor cell populations were severely reduced after ablating Ctcf, c-Kitint common lymphoid progenitors and their progenies were less affected by the lack of CTCF. Whole-transcriptome microarray and cell cycle analyses indicated that CTCF deficiency results in the enhanced expression of the cell cycle-promoting program, and that CTCF-depleted HSCs express higher levels of reactive oxygen species (ROS). Importantly, in vivo treatment with an antioxidant partially rescued c-Kithi cell populations and their quiescence. Altogether, our results suggest that CTCF is indispensable for maintaining adult HSC pools, likely by regulating ROS-dependent HSC quiescence.