JIAN XU LABORATORY

Research Focus

One of the fundamental questions in biology is how gene expression programs are established and maintained to control cell identity. Although we know diseases such as cancer and inherited blood disorders are the results of malfunctions in gene regulation, pinpointing the disease-causing genes and genetic regulatory elements remains difficult. Further complicating this is the epigenetic control of gene function which often contributes to disease pathophysiology.

Our goal is to better understand the gene regulatory processes that control stem cell development and cancers. We employ interdisciplinary approaches including molecular biology, genome engineering, disease modeling, single cell technology and computational biology to discover new mechanisms in gene regulation and genome sciences. By elucidating the basic principles of gene regulation in normal and neoplastic blood cell development, we seek to develop innovative strategies to precisely control gene function and advance diagnosis, prognosis and treatment of human disorders.

Research Projects

Enhancer Biology in Development and Cancer

Epigenetics and Metabolic Control of Hematopoiesis and Leukemia

Non-Coding Genome in Normal and Cancer Stem Cells

Enhancer Biology in Development and Cancer

A fundamental question in biology is how gene expression programs are established and maintained to preserve or alter cell identity. This question is intimately related to how transcription factors interact with the appropriate gene-specific cis-regulatory elements within chromatin.

Enhancers are cis-acting DNA sequences that determine cell identity by regulating when, where and how genes are expressed. Despite their importance, the regulatory components controlling the structure and function of enhancers during lineage development and disease pathogenesis remain largely unknown.

We recently developed the CRISPR/Cas9-based ‘CAPTURE’ system to unbiasedly identify chromatin interactions that regulate non-coding genomic elements including enhancers. Using biotinylated dCas9 and programmable sgRNAs, we were able to selectively isolate the native genomic locus-associated protein complexes and 3D chromatin structures (Liu et al., 2017). The CAPTURE system provides a ‘first-in-kind’ approach to simultaneously identify cis-element-regulating proteins and DNA structures, and compare the results to establish the causality of gene expression during development and disorders.

We also developed dCas9-based enhancer-targeting epigenetic perturbation systems, enCRISPRi and enCRISPRa, for high throughput analyses of enhancer function in lineage differentiation and cancer pathogenesis (Li et al., 2020). Building on these discoveries, it is our long-term goal to demystify the cis-regulatory logics as fundamental principles that control stem cell development and disorders.

 Ongoing studies in our lab include:

  • Elucidating the molecular determinants of lineage-specifying enhancers
  • Functional and mechanistic analysis of pathogenic non-coding variants
  • Developing genomic and epigenomic editing technologies in dissecting genome structure and function

Epigenetics and Metabolic Control of Hematopoiesis and Leukemia

Illustration of Dr. Jian Xu's project: Epigenetics of Blood Stem Cell Development and MalignanciesHow epigenetics and metabolism cooperate to control normal development and disease processes is a fundamentally important question with significant clinical implication. Many epigenetic enzymes catalyzing DNA or histone modifications are susceptible to changes in co-substrates of cellular metabolism, but little is known about whether and how altered epigenetics influences metabolism during cancer progression.

We recently described that inactivation of the histone methyltransferase EZH2 promotes leukemic transformation by aberrant activation of branched-chain amino acid (BCAA) metabolism in leukemia-initiating cells, establishing a new molecular link between altered epigenetics and metabolism in cancer progression (Gu et al., 2019). This study was among the first to show that epigenetic alterations rewire intracellular metabolism during cancer transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells.

In other studies, we compared the proteomic and transcriptomic changes in human primary hematopoietic stem/progenitor cells and erythroid cells, and uncovered pathways related to mitochondrial biogenesis enhanced through protein translation, establishing a new mechanism for post-transcriptional control of mitochondria related to hematologic defects in mitochondrial diseases and aging (Liu et al., 2017).

Building on these findings, we are examining the epigenetic and metabolic liabilities of blood stem cells in development and pathological conditions. Ongoing studies include:

  • BCAA metabolism in stem cell function and cancer development
  • Metabolic control of normal and pathological erythropoiesis
  • Crosstalk between epigenetic gene regulation and intracellular metabolism in hematopoiesis and leukemia

Non-Coding Genome in Normal and Cancer Stem Cells

Advances in genome sequencing are poised for applications in personalized medicine. However, current understanding of disease-causing genetic alterations is largely based on protein-coding DNA sequences consisting of only ~1% of human genome. It remains unclear how alterations within non-coding genome, consisting of various regulatory elements and mobile DNA sequences, contribute to disease pathophysiology. Similarly, genotype-phenotype association studies continue to elucidate non-coding genomic regions that are altered in human diseases, although identification of causal elements remains challenging impeding drug development and therapeutics.

We aim to develop experimental and computational methodologies, and integrate with in vitro and in vivo disease modeling towards a systems-level view of disease-associated non-coding genetic elements in development and diseases. This is possible by mapping genetic and 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 gene regulatory networks in normal and neoplastic hematopoiesis, we aim to investigate how non-coding regulatory genome, lineage-specifying regulators, epigenetic modulators and environmental signals cooperate to control lineage specification, and how dysregulation of these mechanisms contribute to cancer development.

Ongoing studies in our lab include:

  • Oncogenic cooperation between coding and non-coding variants in cancer pathophysiology
  • Integrative analysis of genomic structural variants as cancer drivers
  • Roles and rules of genomic transposable elements in hematopoiesis and leukemia

About Dr. Xu

Jian Xu received his Ph.D. with Dr. Stephen Smale from UCLA, where he studied epigenetic regulation of stem cell pluripotency. In 2008, he joined Dr. Stuart Orkin’s laboratory at Boston Children’s Hospital as a Helen Hay Whitney-HHMI postdoctoral fellow and studied the developmental control of fetal-to-adult hemoglobin switching. In 2012, he became an instructor in Pediatric Hematology-Oncology at Harvard Medical School. His studies with Dr. Orkin provide the first in vivo evidence that genetic inactivation of the zinc finger protein BCL11A is sufficient to ameliorate sickle cell disease (SCD) in preclinical models, and lay the groundwork for ongoing development of gene therapies to target BCL11A for treating patients with inherited hemoglobin disorders.

In 2014, Dr. Xu joined the faculty of the Children’s Medical Center Research Institute at UT Southwestern as an Associate Professor in Pediatrics. Dr. Xu is the recipient of a Helen Hay Whitney Foundation postdoctoral fellowship (2008), an ASH merit award (2009, 2010), a NIH career development award (2011), a CPRIT Scholar in Cancer Research (2014), an ASH Scholar Award (2015) and an LLS Scholar Award (2019).

Curriculum Vitae

Selected Publications

Gu, Z., Liu, Y., Zhang, Y., Cao, H., Lyu, J., Wang, X., Wylie, A., Newkirk, S.J., Jones, A.E., Lee, M., Botten, G.A., Deng, M., Dickerson, K.E., Zhang, C.C., An, W., Abrams, J.M., and Xu J. (2021). Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia. Nat Genet. 53, 672-682. (PubMed)

Li, K., Zhang, Y., Liu, X., Liu, Y., Gu, Z., Cao, H., Dickerson, K.E., Chen, M., Chen, W., Shao, Z., Ni, M., and Xu, J. (2020). Non-coding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies. Cancer Discov. 10, 724-745. (PubMed

Gu, Z., Liu, Y., Cai, F., Patrick, M., Zmajkovic, J., Cao, H., Zhang, Y., Tasdogan, A., Chen, M., Qi, L., Liu, X., Li, K., Lyu, J., Dickerson, K.E., Chen, W., Ni, M., Merritt, M.E., Morrison. S.J., Skoda, R.C., DeBerardinis, R.J., and Xu, J. (2019) Loss of EZH2 reprograms BCAA metabolism to drive leukemic transformation. Cancer Discov. 9, 1228-1247.  (PubMed)

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

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., 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

Giovanni Botten

M.D./Ph.D. Student

Hui Cao, M.S.

Lab Manager/Senior Research Associate

Kathryn Dickerson, M.D., M.S.C.S.

Assistant Professor, Pediatrics

Chelsee Greer, D.O.

Pediatric Hematology/Oncology Fellow

Zhimin Gu, Ph.D.

Assistant Instructor

Pranita Kaphle, M.S.

Research Technician

Yoon, sequencing facility

Yoon Jung Kim, Ph.D.

Research Scientist

Michael Lee Jr.

M.D./Ph.D Student

Junhua Lyu, Ph.D.

Postdoctoral Fellow

McKenzie Patrick

Ph.D. Student

Gen Zhang, Ph.D.

Postdoctoral Fellow

Yuannyu Zhang, Ph.D.

Assistant Professor

Sisi Zheng, M.D.

Instructor, Pediatric Hematology/Oncology

Xin Liu, Ph.D.

Principal Investigator, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences

Postdoctoral Fellow (2014-2019)

Kailong Li, Ph.D.

Principal Investigator, School of Basic Medical Sciences, Peking University

Postdoctoral Fellow (2015-2020)

Yuxuan Liu, Ph.D.

Senior Research Investigator at BeiGene

Postdoctoral Fellow (2016-2020)

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