Hox genes are critical for maintaining the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs). Although ectopic expression of the HoxB4 gene in bone marrow or embryonic stem cells (ESCs) leads to a dramatic expansion and long-term engraftment potential of HSCs, HoxB4 deficient mice exhibit only a mild reduction in progenitors and stem cells in fetal liver and bone marrow. In contrast, mice deficient in both HoxB3 and HoxB4 genes display severe hematopoietic defects with a marked decrease in HSC population indicating that other anterior HoxB genes may cooperate with HoxB4 to specify hematopoietic cell fate. It is important to understand underlying mechanisms by which the anterior HoxB genes are coordinately activated to confer HSC fate. The expression of Hox genes is regulated epigenetically by polycomb (PcG) and trithorax (TrxG) group regulators. We showed that recruitment of SETD1A to the HoxB4 locus governs its transcription activation and promotes HSC fate. Furthermore, we have identified and cloned a HoxB locus associated long intergenic noncoding RNA (lincRNA), HoxBlinc, which is expressed during early hematopoietic differentiation consistent with H3K4me3 patterns and anterior HoxB gene activation. Furthermore, HoxBlinc associates with the Setd1a HMT complex and controls the specification and differentiation of Flk1+ hemangioblasts. Thus, the data suggest that HoxBlinc RNA may play an important role in early hematopoiesis, at least in part by recruiting Setd1a HMT complexes onto the Hox genes thereby modulating Hox locus chromatin structure and organization. However, it remains unknown how HoxBlinc reprograms chromatin state to regulate anterior HoxB genes and hematopoietic specific transcription program and whether HoxBlinc plays a role in targeting histone modifying enzymes to these genes to initiate hematopoietic differentiation. Based on our preliminary data, we hypothesize that selective recruitment of the Setd1a HMT complex to the HoxB locus and coordination of anterior HoxB expression are mediated by HoxBlinc to specify the hematopoietic cell fate. In this proposal, we will examine the role of HoxBlinc in reprograming chromatin state and modulating anterior HoxB gene transcription. We will investigate underlying epigenetic mechanism by which HoxBlinc regulates early hematopoietic lineage commitment and differentiation. By finishing the proposed research, we expect a better understanding of molecular mechanism by which lincRNA and epigenetic regulators control early events of hematopoiesis.

Public Health Relevance

Long noncoding RNAs (lncRNA) are involved in regulating of chromatin state, gene expression, and tissue or organ development. However, it is unknown whether lncRNA plays a role in hematopoietic lineage commitment and differentiation. In this proposal, we will study the underlying molecular mechanisms of the lncRNA HoxBlinc mediated epigenetic modification in Hox gene activation and hematopoietic lineage commitment that will eventually contribute to better understanding of pathogenesis of hematological malignancy and provide new avenues for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK110108-04
Application #
9523246
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2016-07-15
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Shen, Yong; Bassett, MacLean A; Gurumurthy, Aishwarya et al. (2018) Identification of a novel enhancer/chromatin opening element associated with high-level ?-globin gene expression. Mol Cell Biol :
Luo, Huacheng; Wang, Fei; Zha, Jie et al. (2018) CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia. Blood 132:837-848
Jian, Wei; Yan, Bowen; Huang, Suming et al. (2017) Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly. FASEB J 31:4104-4116
Qiu, Yi; Huang, Suming (2017) Catching global interactions in vivo. Cell Biosci 7:49
Li, Xuehui; Mei, Yang; Yan, Bowen et al. (2017) Histone deacetylase 6 regulates cytokinesis and erythrocyte enucleation through deacetylation of formin protein mDia2. Haematologica 102:984-994
Pan, Feng; Wingo, Thomas S; Zhao, Zhigang et al. (2017) Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells. Nat Commun 8:15102