Bio

Academic Appointments


Professional Education


  • Posdoctoral, Stanford University, Genomcis (2014)
  • Postdoctoral, Virginia Commonwealth University, Cancer Biology (2011)

Publications

All Publications


  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria GENETICS IN MEDICINE Nykamp, K., Anderson, M., Powers, M., Garcia, J., Herrera, B., Ho, Y., Kobayashi, Y., Patil, N., Thusberg, J., Westbrook, M., Topper, S., Invitae Clinical Genomics Grp 2017; 19 (10): 1105–17

    Abstract

    PurposeThe 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines were a major step toward establishing a common framework for variant classification. In practice, however, several aspects of the guidelines lack specificity, are subject to varied interpretations, or fail to capture relevant aspects of clinical molecular genetics. A simple implementation of the guidelines in their current form is insufficient for consistent and comprehensive variant classification.MethodsWe undertook an iterative process of refining the ACMG-AMP guidelines. We used the guidelines to classify more than 40,000 clinically observed variants, assessed the outcome, and refined the classification criteria to capture exceptions and edge cases. During this process, the criteria evolved through eight major and minor revisions.ResultsOur implementation: (i) separated ambiguous ACMG-AMP criteria into a set of discrete but related rules with refined weights; (ii) grouped certain criteria to protect against the overcounting of conceptually related evidence; and (iii) replaced the "clinical criteria" style of the guidelines with additive, semiquantitative criteria.ConclusionSherloc builds on the strong framework of 33 rules established by the ACMG-AMP guidelines and introduces 108 detailed refinements, which support a more consistent and transparent approach to variant classification.

    View details for DOI 10.1038/gim.2017.37

    View details for Web of Science ID 000412303300005

    View details for PubMedID 28492532

    View details for PubMedCentralID PMC5632818

  • Mango: a bias-correcting ChIA-PET analysis pipeline. Bioinformatics Phanstiel, D. H., Boyle, A. P., Heidari, N., Snyder, M. P. 2015; 31 (19): 3092-3098

    Abstract

    Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) is an established method for detecting genome-wide looping interactions at high resolution. Current ChIA-PET analysis software packages either fail to correct for non-specific interactions due to genomic proximity or only address a fraction of the steps required for data processing. We present Mango, a complete ChIA-PET data analysis pipeline that provides statistical confidence estimates for interactions and corrects for major sources of bias including differential peak enrichment and genomic proximity.Comparison to the existing software packages, ChIA-PET Tool and ChiaSig revealed that Mango interactions exhibit much better agreement with high-resolution Hi-C data. Importantly, Mango executes all steps required for processing ChIA-PET datasets, whereas ChiaSig only completes 20% of the required steps. Application of Mango to multiple available ChIA-PET datasets permitted the independent rediscovery of known trends in chromatin loops including enrichment of CTCF, RAD21, SMC3 and ZNF143 at the anchor regions of interactions and strong bias for convergent CTCF motifs.Mango is open source and distributed through github at https://github.com/dphansti/mango.mpsnyder@standford.eduSupplementary data are available at Bioinformatics online.

    View details for DOI 10.1093/bioinformatics/btv336

    View details for PubMedID 26034063

  • Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions CELL Grubert, F., Zaugg, J. B., Kasowski, M., Ursu, O., Spacek, D. V., Martin, A. R., Greenside, P., Srivas, R., Phanstiel, D. H., Pekowska, A., Heidari, N., Euskirchen, G., Huber, W., Pritchard, J. K., Bustamante, C. D., Steinmetz, L. M., Kundaje, A., Snyder, M. 2015; 162 (5): 1051-1065

    Abstract

    Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.

    View details for DOI 10.1016/j.cell.2015.07.048

    View details for Web of Science ID 000360589900015

    View details for PubMedCentralID PMC4556133

  • Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions. Cell Grubert, F., Zaugg, J. B., Kasowski, M., Ursu, O., Spacek, D. V., Martin, A. R., Greenside, P., Srivas, R., Phanstiel, D. H., Pekowska, A., Heidari, N., Euskirchen, G., Huber, W., Pritchard, J. K., Bustamante, C. D., Steinmetz, L. M., Kundaje, A., Snyder, M. 2015; 162 (5): 1051-1065

    Abstract

    Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.

    View details for DOI 10.1016/j.cell.2015.07.048

    View details for PubMedID 26300125

  • Genome-wide map of regulatory interactions in the human genome GENOME RESEARCH Heidari, N., Phanstiel, D. H., He, C., Grubert, F., Jahanbani, F., Kasowski, M., Zhang, M. Q., Snyder, M. P. 2014; 24 (12): 1905-1917

    Abstract

    Increasing evidence suggests that interactions between regulatory genomic elements play an important role in regulating gene expression. We generated a genome-wide interaction map of regulatory elements in human cells (ENCODE tier 1 cells, K562, GM12878) using Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) experiments targeting six broadly distributed factors. Bound regions covered 80% of DNase I hypersensitive sites including 99.7% of TSS and 98% of enhancers. Correlating this map with ChIP-seq and RNA-seq data sets revealed cohesin, CTCF, and ZNF143 as key components of three-dimensional chromatin structure and revealed how the distal chromatin state affects gene transcription. Comparison of interactions between cell types revealed that enhancer-promoter interactions were highly cell-type-specific. Construction and comparison of distal and proximal regulatory networks revealed stark differences in structure and biological function. Proximal binding events are enriched at genes with housekeeping functions, while distal binding events interact with genes involved in dynamic biological processes including response to stimulus. This study reveals new mechanistic and functional insights into regulatory region organization in the nucleus.

    View details for DOI 10.1101/gr.176586.114

    View details for PubMedID 25228660

  • Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c-Jun in leukemia cells CELL DEATH & DISEASE Heidari, N., Miller, A. V., Hicks, M. A., Marking, C. B., Harada, H. 2012; 3: e349

    Abstract

    Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria-dependent pathway. BIM (BCL-2-interacting mediator of cell death), a BCL-2 homology 3-only pro-apoptotic protein, is upregulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia cells and has an essential role in Dex-induced apoptosis. It has been indicated that Dex-induced BIM is regulated mainly by transcription, however, the molecular mechanisms including responsible transcription factors are unclear. In this study, we found that Dex treatment induced transcription factor Runx2 and c-Jun in parallel with BIM induction. Dex-induced BIM and apoptosis were decreased in cells harboring dominant-negative c-Jun and were increased in cells with c-Jun overexpression. Cells harboring short hairpin RNA for Runx2 also decreased BIM induction and apoptosis. On the Bim promoter, c-Jun bound to and activated the AP-1-binding site at about -2.7 kb from the transcription start site. Treatment with RU486, a GC receptor antagonist, blocked Dex-induced Runx2, c-Jun and BIM induction, as well as apoptosis. Furthermore, pretreatment with SB203580, a p38-mitogen-activated protein kinase (MAPK) inhibitor, decreased Dex-induced Runx2, c-Jun and BIM, suggesting that p38-MAPK activation is upstream of the induction of these molecules. In conclusion, we identified the critical signaling pathway for GC-induced apoptosis, and targeting these molecules may be an alternative approach to overcome GC-resistance in leukemia treatment.

    View details for DOI 10.1038/cddis.2012.89

    View details for Web of Science ID 000306786400012

    View details for PubMedID 22825467

    View details for PubMedCentralID PMC3406588

  • GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy CELL DEATH & DISEASE Heidari, N., Hicks, M. A., Harada, H. 2010; 1: e76

    Abstract

    Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies including acute lymphoblastic leukemia (ALL). The BCL-2 family has an essential role in regulating GC-induced cell death. Here we show that downregulation of antiapoptotic BCL-2 family proteins, especially MCL-1, enhances GC-induced cell death. Thus we target MCL-1 by using GX15-070 (obatoclax) in ALL cells. Treatment with GX15-070 in both dexamethasone (Dex)-sensitive and -resistant ALL cells shows effective growth inhibition and cell death. GX15-070 induces caspase-3 cleavage and increases the Annexin V-positive population, which is indicative of apoptosis. Before the onset of apoptosis, GX15-070 induces LC3 conversion as well as p62 degradation, both of which are autophagic cell death markers. A pro-apoptotic molecule BAK is released from the BAK/MCL-1 complex following GX15-070 treatment. Consistently, downregulation of BAK reduces caspase-3 cleavage and cell death, but does not alter LC3 conversion. In contrast, downregulation of ATG5, an autophagy regulator, decreases LC3 conversion and cell death, but does not alter caspase-3 cleavage, suggesting that apoptosis and autophagy induced by GX15-070 are independently regulated. Downregulation of Beclin-1, which is capable of crosstalk between apoptosis and autophagy, affects GX15-070-induced cell death through apoptosis but not autophagy. Taken together, GX15-070 treatment in ALL could be an alternative regimen to overcome glucocorticoid resistance by inducing BAK-dependent apoptosis and ATG5-dependent autophagy.

    View details for DOI 10.1038/cddis.2010.53

    View details for Web of Science ID 000282361700008

    View details for PubMedID 21364679

    View details for PubMedCentralID PMC3032343