- Browse by Author
Browsing by Author "Wang, Jianlong"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells(SpringerNature, 2017-04-25) Pan, Feng; Wingo, Thomas S.; Zhao, Zhigang; Gao, Rui; Makishima, Hideki; Qu, Guangbo; lin, Li; Yu, Miao; Ortega, Janice R.; Wang, Jiapeng; Nazha, Aziz; Chen, Li; Yao, Bing; Liu, Can; Chen, Shi; Weeks, Ophelia; Ni, Hongyu; Phillips, Brittany Lynn; Huang, Suming; Wang, Jianlong; He, Chuan; Li, Guo-Min; Radivoyevitch, Tomas; Aifantis, Iannis; Maciejewski, Jaroslaw P.; Yang, Feng-Chun; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, School of MedicineTET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2-/- tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2-/- Lin-c-Kit+ cells shows higher mutation frequencies in Tet2-/- cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis.Item Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a(Nature Publishing Group, 2018-07-03) Kim, Kun-Yong; Tanaka, Yoshiaki; Su, Juan; Cakir, Bilal; Xiang, Yangfei; Patterson, Benjamin; Ding, Junjun; Jung, Yong-Wook; Kim, Ji-Hyun; Hysolli, Eriona; Lee, Haelim; Dajani, Rana; Kim, Jonghwan; Zhong, Mei; Lee, Jeong-Heon; Skalnik, David; Lim, Jeong Mook; Sullivan, Gareth J.; Wang, Jianlong; Park, In-Hyun; Biology, School of ScienceEmbryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Investigating how epigenetic regulation controls lineage specification is critical in order to generate the required cell types for clinical applications. Uhrf1 is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt1 and in heterochromatin formation alongside G9a, Trim28, and HDACs. Although Uhrf1 is not essential in ESC self-renewal, it remains elusive how Uhrf1 regulates cell specification. Here we report that Uhrf1 forms a complex with the active trithorax group, the Setd1a/COMPASS complex, to maintain bivalent histone marks, particularly those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards proper differentiation via bivalent histone modifications.