Bio

Honors & Awards


  • Ann Schreiber Research Training Program of Excellence Grantee, Ovarian Cancer Research Fund (2013-2014)
  • Graduate Fellowship, National Science Foundation (2002-2005)
  • Postdoctoral Fellowship, Helen Hay Whitney Foundation (2010-2013)

Professional Education


  • Doctor of Philosophy, Yale University, Immunobiology (2009)
  • Bachelor of Science, Haverford College, Chemistry (2000)

Stanford Advisors


Publications

Journal Articles


  • BAF complexes facilitate decatenation of DNA by topoisomerase IIa. Nature Dykhuizen, E. C., Hargreaves, D. C., Miller, E. L., Cui, K., Korshunov, A., Kool, M., Pfister, S., Cho, Y., Zhao, K., Crabtree, G. R. 2013; 497 (7451): 624-627

    Abstract

    Recent exon-sequencing studies of human tumours have revealed that subunits of BAF (mammalian SWI/SNF) complexes are mutated in more than 20% of all human malignancies, but the mechanisms involved in tumour suppression are unclear. BAF chromatin-remodelling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb repressive complex 2 (PRC2) across the genome. Several proteins dedicated to this multisubunit complex, including BRG1 (also known as SMARCA4) and BAF250a (also known as ARID1A), are mutated at frequencies similar to those of recognized tumour suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastomas and more than 15% of Burkitt's lymphomas. Here we show a previously unknown function of BAF complexes in decatenating newly replicated sister chromatids, a requirement for proper chromosome segregation during mitosis. We find that deletion of Brg1 in mouse cells, as well as the expression of BRG1 point mutants identified in human tumours, leads to anaphase bridge formation (in which sister chromatids are linked by catenated strands of DNA) and a G2/M-phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes interact directly with endogenous topoisomerase II? (TOP2A) through BAF250a and are required for the binding of TOP2A to approximately 12,000 sites across the genome. Our results demonstrate that TOP2A chromatin binding is dependent on the ATPase activity of BRG1, which is compromised in oncogenic BRG1 mutants. These studies indicate that the ability of TOP2A to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumour suppressors.

    View details for DOI 10.1038/nature12146

    View details for PubMedID 23698369

  • Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nature genetics Kadoch, C., Hargreaves, D. C., Hodges, C., Elias, L., Ho, L., Ranish, J., Crabtree, G. R. 2013; 45 (6): 592-601

    Abstract

    Subunits of mammalian SWI/SNF (mSWI/SNF or BAF) complexes have recently been implicated as tumor suppressors in human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of endogenous mSWI/SNF complexes, which identified several new dedicated, stable subunits not found in yeast SWI/SNF complexes, including BCL7A, BCL7B and BCL7C, BCL11A and BCL11B, BRD9 and SS18. Incorporating these new members, we determined mSWI/SNF subunit mutation frequency in exome and whole-genome sequencing studies of primary human tumors. Notably, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, mutations affecting more than one subunit, defined here as compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer, exhibiting a broad mutation pattern, similar to that of TP53. Thus, proper functioning of polymorphic BAF complexes may constitute a major mechanism of tumor suppression.

    View details for DOI 10.1038/ng.2628

    View details for PubMedID 23644491

  • ATP-dependent chromatin remodeling: genetics, genomics and mechanisms CELL RESEARCH Hargreaves, D. C., Crabtree, G. R. 2011; 21 (3): 396-420

    Abstract

    Macromolecular assemblies that regulate chromatin structure using the energy of ATP hydrolysis have critical roles in development, cancer, and stem cell biology. The ATPases of this family are encoded by 27 human genes and are usually associated with several other proteins that are stable, non-exchangeable subunits. One fundamental mechanism used by these complexes is thought to be the movement or exchange of nucleosomes to regulate transcription. However, recent genetic studies indicate that chromatin remodelers may also be involved in regulating other aspects of chromatin structure during many cellular processes. The SWI/SNF family in particular appears to have undergone a substantial change in subunit composition and mechanism coincident with the evolutionary advent of multicellularity and the appearance of linking histones. The differential usage of this greater diversity of mammalian BAF subunits is essential for the development of specific cell fates, including the progression from pluripotency to multipotency to committed neurons. Recent human genetic screens have revealed that BRG1, ARID1A, BAF155, and hSNF5 are frequently mutated in tumors, indicating that BAF complexes also play a critical role in the initiation or progression of cancer. The mechanistic bases underlying the genetic requirements for BAF and other chromatin remodelers in development and cancer are relatively unexplored and will be a focus of this review.

    View details for DOI 10.1038/cr.2011.32

    View details for Web of Science ID 000288064900004

    View details for PubMedID 21358755

  • Control of Inducible Gene Expression by Signal-Dependent Transcriptional Elongation CELL Hargreaves, D. C., Horng, T., Medzhitov, R. 2009; 138 (1): 129-145

    Abstract

    Most inducible transcriptional programs consist of primary and secondary response genes (PRGs and SRGs) that differ in their kinetics of expression and in their requirements for new protein synthesis and chromatin remodeling. Here we show that many PRGs, in contrast to SRGs, have preassembled RNA polymerase II (Pol II) and positive histone modifications at their promoters in the basal state. Pol II at PRGs generates low levels of full-length unspliced transcripts but fails to make mature, protein-coding transcripts in the absence of stimulation. Induction of PRGs is controlled at the level of transcriptional elongation and mRNA processing, through the signal-dependent recruitment of P-TEFb. P-TEFb is in turn recruited by the bromodomain-containing protein Brd4, which detects H4K5/8/12Ac inducibly acquired at PRG promoters. Our findings suggest that the permissive structure of PRGs both stipulates their unique regulation in the basal state by corepressor complexes and enables their rapid induction in multiple cell types.

    View details for DOI 10.1016/j.cell.2009.05.047

    View details for Web of Science ID 000267848600020

    View details for PubMedID 19596240

  • Gene-specific control of inflammation by TLR-induced chromatin modifications NATURE Foster, S. L., Hargreaves, D. C., Medzhitov, R. 2007; 447 (7147): 972-U4

    Abstract

    Toll-like receptors (TLRs) induce a multi-component inflammatory response that must be tightly regulated to avoid tissue damage. Most known regulatory mechanisms target TLR signalling pathways and thus broadly inhibit multiple aspects of the inflammatory response. Given the functional diversity of TLR-induced genes, we proposed that additional, gene-specific regulatory mechanisms exist to allow individual aspects of the TLR-induced response to be differentially regulated. Using an in vitro system of lipopolysaccharide tolerance in murine macrophages, we show that TLR-induced genes fall into two categories on the basis of their functions and regulatory requirements. We demonstrate that representatives from the two classes acquire distinct patterns of TLR-induced chromatin modifications. These gene-specific chromatin modifications are associated with transient silencing of one class of genes, which includes pro-inflammatory mediators, and priming of the second class, which includes antimicrobial effectors. These findings illustrate an adaptive response in macrophages and reveal component-specific regulation of inflammation.

    View details for DOI 10.1038/nature05836

    View details for Web of Science ID 000247373100040

    View details for PubMedID 17538624

  • Innate sensors of microbial infection JOURNAL OF CLINICAL IMMUNOLOGY Hargreaves, D. C., Medzhitov, R. 2005; 25 (6): 503-510

    Abstract

    The innate immune system utilizes multiple families of pattern-recognition receptors (PRRs) to protect the host from infection. Each of these families contributes certain elements to the complement of innate effector functions that is elicited during an infection. Here we review the families of PRRs and explore examples of their cooperativity.

    View details for DOI 10.1007/s10875-005-8065-4

    View details for Web of Science ID 000234273800001

    View details for PubMedID 16380814

  • Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis JOURNAL OF IMMUNOLOGY Luther, S. A., Bidgol, A., Hargreaves, D. C., Schmidt, A., Xu, Y., Paniyadi, J., Matloubian, M., Cyster, J. G. 2002; 169 (1): 424-433

    Abstract

    Despite their widespread expression, the in vivo recruitment activities of CCL19 (EBV-induced molecule 1 ligand chemokine) and CXCL12 (stromal cell-derived factor 1) have not been established. Furthermore, although CXCL13 (B lymphocyte chemoattractant) has been shown to induce lymphoid neogenesis through induction of lymphotoxin (LT)alpha1beta2, it is unclear whether other homeostatic chemokines have this property. In this work we show that ectopic expression in pancreatic islets of CCL19 leads to small infiltrates composed of lymphocytes and dendritic cells and containing high endothelial venules and stromal cells. Ectopic CXCL12 induced small infiltrates containing few T cells but enriched in dendritic cells, B cells, and plasma cells. Comparison of CCL19 transgenic mice with mice expressing CCL21 (secondary lymphoid tissue chemokine) revealed that CCL21 induced larger and more organized infiltrates. A more significant role for CCL21 is also suggested in lymphoid tissues, as CCL21 protein was found to be present in lymph nodes and spleen at much higher concentrations than CCL19. CCL19 and CCL21 but not CXCL12 induced LTalpha1beta2 expression on naive CD4 T cells, and treatment of CCL21 transgenic mice with LTbetaR-Fc antagonized development of organized lymphoid structures. LTalpha1beta2 was also induced on naive T cells by the cytokines IL-4 and IL-7. These studies establish that CCL19 and CXCL12 are sufficient to mediate cell recruitment in vivo and they indicate that LTalpha1beta2 may function downstream of CCL21, CCL19, and IL-2 family cytokines in normal and pathological lymphoid tissue development.

    View details for Web of Science ID 000176360400054

    View details for PubMedID 12077273

  • Traffic patterns of B cells and plasma cells LYMPHOCYTE ACTIVATION AND IMMUNE REGULATION IX Cyster, J. G., Ansel, K. M., Ngo, V. N., Hargreaves, D. C., Lu, T. T. 2002; 512: 35-41

    View details for Web of Science ID 000179161600005

    View details for PubMedID 12405185

  • A coordinated change in chemokine responsiveness guides plasma cell movements JOURNAL OF EXPERIMENTAL MEDICINE Hargreaves, D. C., Hyman, P. L., Lu, T. T., Ngo, V. N., Bidgol, A., Suzuki, G., Zou, Y. R., Littman, D. R., Cyster, J. G. 2001; 194 (1): 45-56

    Abstract

    Antibody-secreting plasma cells are nonrecirculatory and lodge in splenic red pulp, lymph node medullary cords, and bone marrow. The factors that regulate plasma cell localization are poorly defined. Here we demonstrate that, compared with their B cell precursors, plasma cells exhibit increased chemotactic sensitivity to the CXCR4 ligand CXCL12. At the same time, they downregulate CXCR5 and CCR7 and have reduced responsiveness to the B and T zone chemokines CXCL13, CCL19, and CCL21. We demonstrate that CXCL12 is expressed within splenic red pulp and lymph node medullary cords as well as in bone marrow. In chimeric mice reconstituted with CXCR4-deficient fetal liver cells, plasma cells are mislocalized in the spleen, found in elevated numbers in blood, and fail to accumulate normally in the bone marrow. Our findings indicate that as B cells differentiate into plasma cells they undergo a coordinated change in chemokine responsiveness that regulates their movements in secondary lymphoid organs and promotes lodgment within the bone marrow.

    View details for Web of Science ID 000169749800005

    View details for PubMedID 11435471

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