XU LAB

Research Focus

The relationship between genetics and disease is complex. Although we know diseases such as cancer and inherited blood disorders are the result of mutations in gene function, pinpointing these disease-associated genes and understanding how gene networks contribute to disease pathophysiology is difficult. Further complicating this is the presence of epigenetic alterations which often drive cancer progression.

Understanding how these mechanisms interact to control stem cell development and cancer progression is fundamental to developing new therapies. Our research focuses on blood cell development and how abnormalities can cause cancers such as childhood leukemia. We seek to advance our understanding of the basic principles of gene regulation in normal and neoplastic blood cell development, and provide critical insights into developing novel therapeutic approaches for target-based cancer interventions.

Research Projects

Epigenetics of Blood Stem Cell Development and Malignancies

Enhancer Composition and Mechanisms During Hematopoiesis

The Role of the Noncoding Genome in Hematopoiesis and Leukemogenesis

Epigenetics of Blood Stem Cell Development and Malignancies

Epigenetic machinery plays crucial roles in gene expression and stem cell development, and its deregulation drives the development of human disorders. Polycomb Repressive Complex 2 (PRC2) is a major class of epigenetic regulator that catalyzes the di/tri-methylation of histone H3 lysine 27 (or H3K27me2/3). The canonical PRC2 complex consists of EED, SUZ12 and the histone methyltransferases EZH1 and EZH2.

Overexpression or gain-of-function of PRC2 proteins is common in many cancers, and inactivating mutations of PRC2 components have also been described in various hematopoietic malignancies. This raises major questions about how this complex mediates oncogenic and tumor suppressive activities in different cellular contexts.

In light of recent efforts to therapeutically target EZH2 activities or canonical EZH2-PRC2 functions in various human cancers, it is critical to fully understand the context-dependent activity of this complex in order to rationally target it and to improve outcomes.

Ongoing projects in our lab include a wide variety of functional epigenomic approaches coupled with genomic engineering and in vivo disease modeling to define cell-type-specific gene targets, partner proteins and cellular pathways associated with canonical and non-canonical PRC2 complexes in normal and neoplastic development.

These results will help further clarify the complex epigenetic mechanisms in blood cell differentiation and facilitate the development of epigenetic therapeutics for cancer treatment.

Enhancer Composition and Mechanisms During Hematopoiesis

Transcriptional enhancers are the primary determinants of temporal and tissue-specific gene expression and influence a variety of cellular processes. Enhancers are formed through cooperative and synergistic binding of multiple transcription factors, DNA binding effectors of signaling pathways and chromatin modifying complexes. The molecular processes controlling enhancer activation (“commissioning”) and deactivation (“decommissioning”) during stem cell development remain largely unknown.

We believe that modeling human hematopoiesis ex vivo combined with epigenomic enhancer annotation and analysis of the underlying DNA sequences can be used as an unbiased approach to identify causative transcriptional factors (TFs) and their combinatorial rules driving gene programs in distinct blood cell types during development. As a proof of concept of this approach, we are focusing on elucidating enhancer-centered regulatory networks governing human fetal and adult blood stem cell development.

Ongoing projects in our lab include:

  • Identifying lineage and developmental stage-specific enhancer elements.
  • Analysis of regulatory sequences for functionally relevant TFs and their combinatorial patterns.
  • Employing functional and genetic approaches to decipher the causative noncoding regulatory elements controlling blood stem cell functions.

Findings from these studies will provide critical insights into the enhancer dynamics and mechanisms directing cell fate transitions during lineage programming and reprogramming.

The Role of the Noncoding Genome in Hematopoiesis and Leukemogenesis

Advances in genome sequencing are poised for applications in personalized medicine. Currently, efforts focus on protein-coding sequences consisting of less than two percent of the human genome. It remains unclear how alterations within the noncoding genome, such as transcriptional enhancers, contribute to cancer pathophysiology. This lack of understanding impedes the development of new drug and treatments.

We aim to develop experimental and computational methodologies and integrate them with in vitro and in vivo disease modeling to create a systems-level view of the role of disease-associated noncoding genomic elements in normal development and disease progression. This is possible by mapping epigenetic events that discriminate the normal and neoplastic genomes, coupling epigenetic changes with genetic lesions and gene expression programs, and conducting mechanistic studies of individual candidates in disease models.

By comparing the regulatory composition of enhancer-mediated gene networks in normal and neoplastic hematopoiesis, our lab will investigate how noncoding regulatory genome, lineage-specifying regulators, epigenetic modulators and environmental signals cooperate to control lineage specification and how dysregulation of enhancer activities contribute to cancer development.

About Dr. Xu

Jian Xu received his Ph.D. with Dr. Stephen Smale from UCLA, where he studied epigenetic regulation of stem cell pluripotency. Upon completion of his Ph.D. training in 2008, he earned a Helen Hay Whitney Foundation postdoctoral fellowship and joined Dr. Stuart Orkin’s laboratory at Boston Children’s Hospital, Howard Hughes Medical Institute. In 2012, he became an instructor in pediatric hematology-oncology at Harvard Medical School. With Dr. Orkin, he made important discoveries toward understanding the clinically relevant fetal-to-adult developmental globin switch and the epigenetic control of blood stem cell development.

In 2014, Dr. Xu received a first-time investigator award from the Cancer Prevention and Research Institute of Texas and joined the faculty of the Children’s Medical Center Research Institute at UT Southwestern as an Assistant Professor in Pediatrics.

Selected Publications

Liu, X., Zhang, Y., Chen, Y., Li, M., Zhou, F.#, Li ,K., Cao, H., Ni, M., Liu, Y., Gu, Z., Dickerson, K.E., Xie, S., Hon, G.C., Xuan, Z., Zhang, M.Q., Shao, Z., and Xu, J#. (2017) In situ capture of chromatin interactions by biotinylated dCas9. Cell  170, 1028–1043.  (PudMed)  #corresponding author

Liu, X., Zhang, Y., Ni, M., Cao, H., Signer, R.A.J., Li, D., Li, M., Gu, Z., Hu, Z., Dickerson, K.E., Weinberg, S.E., Chandel, N.S., DeBerardinis, R.J., Zhou, F.#, Shao, Z.#., and Xu, J.#. (2017). Mitochondrial biogenesis in erythropoiesis is regulated by mTORC1-mediated protein translation. Nat. Cell Biol. 19, 626-638(PubMed) #corresponding author

Luc, S., Huang, J., McEldoon, J.L., Somuncular, E., Li, D., Rhodes, C., Mamoor, S., Hou, S., Xu, J.#, and Orkin, S.H.#. (2016). Bcl11a-deficiency leads to hematopoietic stem cell defects with aging-like phenotype. Cell Reports 16, 3181-3194. (PubMed) #corresponding author

Huang, J., Liu, X., Li, D., Shao, Z., Cao, H., Zhang, Y., Trompouki, E., Bowman, T.V., Zon, L.I., Yuan, G.C., Orkin, S.H.#., and Xu, J.#. (2016). Dynamic control of enhancer repertoires drives lineage and stage-specific transcription during hematopoiesis. Dev Cell 36, 9—23. (PubMed) #corresponding author

Xu, J.*, Shao, Z.*, Li, D., Xie, H., Kim, W., Huang, J., Taylor, J.E., Pinello, L., Glass, K., Jaffe, J.D., et al. (2015). Developmental control of Polycomb subunit composition by GATA factors mediates a switch to non-canonical functions. Mol Cell 57, 304—316. (PubMed) *co-first author

Xu. J.*., Shao, Z.*., Glass, K., Bauer, D.E., Pinello, L., Handel, B.V., Hou, S., Stamatoyannopoulos, J.A., Mikkola, H.K.A., Yuan, G.C., and Orkin, S.H. (2012). Combinatorial assembly of developmental stage-specific enhancers controls gene expression programs during human erythropoiesis. Dev Cell 23, 796-811. (PubMed) *co-first author

Xu, J., Peng, C., Sankaran, V.G., Shao, Z., Esrick, E.B., Chong, B.G., Ippolito, G.C., Fujiwara, Y., Ebert, B.L., Tucker, P.W., and Orkin, S.H. (2011). Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science 334, 993-996. (PubMed)

Sankaran, V.G.*., Xu,.J.*., Ragoczy, T., Ippolito, G.C., Walkley, C.R., Maika, S.D., Fujiwara, Y., Ito, M., Groudine, M., Bender, M.A., Tucker, P.W., and Orkin, S.H. (2009). Developmental and species-divergent globin switching are driven by BCL11A. Nature 460, 1093-1097. (PubMed) *co-first author


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Lab Members

Hui Cao, M.S.

Hui Cao, M.S.

Lab Manager/Research Associate

Kathryn Dickerson, M.D.

Kathryn Dickerson, M.D.

Assistant Instructor, Pediatrics

Zhimin Gu, Ph.D.

Zhimin Gu, Ph.D.

Assistant Instructor

Kailong Li, Ph.D.

Kailong Li, Ph.D.

Postdoctoral Fellow

Xin Liu, Ph.D.

Xin Liu, Ph.D.

Postdoctoral Fellow

Yuxuan Liu, Ph.D.

Yuxuan Liu, Ph.D.

Postdoctoral Fellow

Yuannyu Zhang, Ph.D.

Yuannyu Zhang, Ph.D.

Postdoctoral Fellow