The human body is comprised of a large collection of diverse cell types, each providing a specialized and context-specific function. The advent of high-throughput single-cell transcriptomics, has enabled unbiased categorization of diverse developmental and diseased cellular trajectories. However, with current genome-wide approaches, little can be done to understand: i) how cells vary through time, ii) how this variance effects cellular decisions and iii) how TFs affect the activity of regulatory elements (trans) and, in turn, how these elements lead to functional expression differences (cis). Our lab seeks to address these challenges by developing the next-generation of biological tools, tools that integrate molecular biology, microscopy and large-scale bioinformatics to provide a systems-level understanding of single-cells.
Developing new ‘-omic’ technologies
Our group employs a mix set of skills relating to molecular biology, device engineering and microscopy. We use these skills to leverage sequencing technologies to make high-throughput measurements that seek to better understand gene regulation within living systems. For example, in previous work, we have developed RNA-MaP and Assay for Transpose Accessible Chromatin (ATAC-seq). Notably, ATAC-seq has become an increasingly popular method to measure genome-wide chromatin accessibility, i.e. the epigenome. Recently, we have also adapted this method to profile the epigenomes of single-cells (scATAC-seq). We are actively developing technological tools for improving the quality and throughput of these measurements, as well as integrating scATAC-seq with other single-cell ‘-omic’ measurements.
Advanced computation for inferring ‘causative’ gene networks
With the development of novel technologies comes the possibility of new discoveries and subsequently the need for new computational tools. We develop computational solutions to support these novel technologies. Notable examples include methods for high-content image-analysis, nucleosome calling and single-cell epigenomics. Now, we look to build new computational methods that focus on integrating ensemble and single-cell ‘-omics’ data to infer causative gene networks. Such networks will seek to model governing cis and trans effectors of dynamic cell function.
Application to dynamic biological systems
These efforts coalesce into our studies of dynamic cellular systems. While we have a broad interest in human development and disease, we currently focus on leukemia and early human hematopoiesis, however, our efforts are largely collaborative and we welcome new endeavors. In previous work, we have used some of the experimental and computational methods described above to both understand molecular effectors that govern hematopoietic cell fate and in addition we use these findings to better understand the ontogeny of the human cancer, Acute Myeloid Leukemia (AML).
For a full list see: PubMed or Google Scholar
- Buenrostro JD*, Corces R, Lareau C, Wu B, Schep AN, Aryee MJ, Majeti R, Chang HY, Greenleaf WJ*. Integrated Single-Cell Analysis Maps the Continuous Regulatory Landscape of Human Hematopoietic Differentiation. Cell (2018). (*co-corresponding)
- Satpathy AT*, Saligrama N*, Buenrostro JD*, Wei Y, Wu B, Rubin AJ, Granja JM, Li R, Mumbach MR, Lareau CA, Serratelli WS, Gennert DG, Schep AN, Corces MR, Kim YH, Khavari PA, Greenleaf WJ, Davis MM, Chang HY. Transcript-indexed ATAC-seq for precision immune profiling. Nature Medicine (2018). (*equal contribution)
- Lareau CA*, Ulirsch JC*, Bao EL*, Ludwig LS, Guo MH, Benner C, Satpathy AT, Salem R, Hirschhorn JN, Finucane HK, Aryee MJ, Buenrostro JD+, Sankaran VG+. Interrogation of human hematopoiesis at single-cell and single-variant resolution. bioRxiv (2018). (*equal contribution) (+co-corresponding)
- Schep AN, Wu B, Buenrostro JD*, Greenleaf WJ*. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nature Methods (2017). (*co-corresponding)
• Top 10 paper to read in RECOMB/ISCB
- Corces MR* & Buenrostro JD*+, Wu B, Greenside PG, Chan SM, Koenig JL, Snyder MP, Pritchard JK, Kundaje A, Greenleaf WJ, Majeti R+, Chang HY+. Lineage-specific and single cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nature Genetics (2016). (*equal contribution) (+co-senior)
• Featured in Nature Biotech
- Buenrostro JD, Wu B, Litzenburger U, Gonzales M, Ruff D, Snyder M, Chang HY, Greenleaf WJ. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature (2015).
• Featured in Genome Biol. and Nature Methods.
- Schep AN, Buenrostro JD, Denny SK, Schwartz K, Sherlock G, Greenleaf WJ. Structured nucleosome fingerprints enable high-resolution mapping of chromatin architecture within regulatory regions. Genome Research (2015).
- Buenrostro JD* & Araya CL*, Chircus LM, et al. Quantitative analysis of RNA-protein interactions on a massively parallel array reveals biophysical and evolutionary landscapes. Nature Biotechnology (2014). (*equal contribution)
• Selected as the cover for Nature Biotechnology and featured in Nature Methods
- Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nature Methods (2013).
• Featured in Nature Methods and voted most influential paper by RECOMB/ISCB
- Carpenter ML, Buenrostro JD, Valdiosera C, et al. Pulling out the 1%: Whole-Genome Capture for the Targeted Enrichment of Ancient DNA Sequencing Libraries. The American Journal of Human Genetics (2013).
• Featured in Science and Nature Genetics
- Myllykangas S* & Buenrostro JD*, Natsoulis G, Bell JM, Ji HP. Efficient targeted resequencing of human germline and cancer genomes by oligonucleotide-selective sequencing. Nature Biotechnology (2011). (*equal contribution)
- Mor N, Rais Y, Sheban D, Peles S, Aguilera-Castrejon A, Zviran A, Elinger D, Viukov S, Geula S, Krupalnik V, Zerbib M, Chomsky E, Lasman L, Shani T, Bayerl J, Gafni O, Hanna S, Buenrostro JD, Hagai T, Masika, Vainorius G, Bergman Y, Greenleaf WJ, Esteban MA, Elling U, Levin Y, Massarwa R, Merbl Y, Novershtern N, Hanna JH. Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency. Cell Stem Cell (2018).
- Chihara N, Madi A, Kondo T, Zhang H, Acharya N, Singer M, Nyman J, Marjanovic ND, Kowalczyk MS, Wang C, Kurtulus S, Law T, Etminan Y, Nevin J, Buckley CD, Burkett PR, Buenrostro JD, Rozenblatt-Rosen O, Anderson AC, Regev A, Kuchroo CK. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature (2018).
- Finucane HK, Reshef YA, Anttila V, Slowikowski K, Gusev A, Byrnes A, Gazal S, Loh P, Lareau C, Shoresh N, Genovese G, Saunders A, Macosko E, Pollack S, The Brainstorm Consortium, Perry JRB, Buenrostro JD, Bernstein BE, Raychaudhuri S, McCarroll S, Neale BM, Price AL. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nature Genetics (2018).
- Koh AS, Miller EL, Buenrostro JD, Moskowitz DM, Wang J, Greenleaf WJ, Chang HY, Crabtree WJ. Rapid chromatin repression by Aire provides precise control of immune tolerance. Nature Immunology (2018).
- Daugherty AC, Yeo RW, Buenrostro JD, Greenleaf WJ, Kundaje A, Brunet A. Chromatin accessibility dynamics reveal novel functional enhancers in C. elegans. Genome Research (2017).
- Soto-Feliciano YM, Bartlebaugh JME, Liu Y, Sánchez-Rivera FJ, Bhutkar A, Weintraub AS, Buenrostro JD, Cheng CS, Regev A, Jacks TE, Young RA, Hemann MT. PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes. Genes & Dev. (2017).
- She R, Chakravarty AK, Layton CJ, Chircus LM, Andreasson JO, Damaraju N, McMahon PL, Buenrostro JD, Jarosz DF, Greenleaf WJ. Comprehensive and quantitative mapping of RNA-protein interactions across a transcribed eukaryotic genome. PNAS (2017).
- Miller EL, Hargreaves DC, Kadoch C, Chang CY, Calarco JP, Hodges C, Buenrostro JD, Cui K, Greenleaf WJ, Zhao K, Crabtree GR. TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nat Struct Mol Biol. (2017).
- Moskowitz DM, Zhang DW, Hu B, Le Saux S, Yanes RE, Ye Z, Buenrostro JD, Weyand CM, Greenleaf WJ, Goronzy JJ. Epigenomics of human CD8 T cell differentiation and aging. Science Immunology (2017).
- Litzenburger UM, Buenrostro JD, Wu B, Shen Y, Sheffield NC, Kathiria A, Greenleaf WJ, Chang HY. Single-cell epigenomic variability reveals functional cancer heterogeneity. Genome Biol (2017).
- Guo MH, Nandakumar SK, Ulirsch JC, Zekavat SM, Buenrostro JD, Natarajan P, Salem RM, Chiarle R, Mitt M, Kals M, Pärn K, Fischer K, Milani L, Mägi R, Palta P, Gabriel SB, Metspalu A, Lander ES, Kathiresan S, Hirschhorn JN, Esko T, Sankaran VG. Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms. PNAS (2017).
- Chen X, Shen Y, Draper W, Buenrostro JD, Litzenburger U, Cho SW, Satpathy AT, Carter AC, Ghosh RP, East-Seletsky A, Doudna JA, Greenleaf WJ, Liphardt JT, Chang HY. ATAC-see reveals the accessible genome by transposase-mediated imaging and sequencing. Nature Methods (2016).
- Mazumdar C, Shen Y, Xavy S, Zhao F, Reinisch A, Li R, Corces M R, Flynn R A, Buenrostro JD, Chan SM, Thomas D, Koenig JL, Hong WJ, Chang HY, Majeti R. Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation. Cell Stem Cell (2015).
- Maza I, Caspi I, Zviran A, Chmosky E, Rais Y, Viukov S, Geula S, Buenrostro JD, Weinberger L, Krupalnik V, Zerbib M, Dutton JR, Greenleaf WJ, Massarwa R, Novershtern N and Hanna JH. Transient Acquisition of Pluripotency During Somatic Cell Transdifferentiation with iPSC Reprogramming Factors. Nature Biotechnology (2015).
- Buenrostro JD, Wu B, Chang HY, Greenleaf WJ. ATAC-seq: A method for Assaying Chromatin Accessibility Genome-wide. Curr. Protoc. Mol. Biol. (2015).
- Couthouis J, Raphael AR, Siskind C, Findlay AR, Buenrostro JD, Greenleaf WJ, et al. Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy. Neuromuscular Disorders (2014).
- Myllykangas S, Buenrostro J, Ji HP. Overview of Sequencing Technology Platforms. Rodriguez-Expeleta N, Hackenberg M, Aransay A, Bioinformatics for High Throughput Sequencing. p11-26. Springer (2012).
- Flaherty P, Natsoulis G, Muralidharan O, Winters M, Buenrostro J, Bell J, et al. Ultrasensitive detection of rare mutations using next-generation targeted resequencing. Nucleic Acids Res (2012).
- Natsoulis G, Bell JM, Xu H, Buenrostro JD, Ordonez H, et al. A Flexible Approach for Highly Multiplexed Candidate Gene Targeted Resequencing. PLoS ONE (2011).
- Dick CA, Buenrostro J, Butler T, Carlson ML, Kliebenstein DJ, Whittall JB. Arctic Mustard Flower Color Polymorphism Controlled by Petal-Specific Downregulation at the Threshold of the Anthocyanin Biosynthetic Pathway. PLoS ONE (2011).
- Whittall JB, Syring J, Parks M, Buenrostro J, Dick C, Liston A, Cronn R. Finding a (pine) needle in a haystack: chloroplast genome sequence divergence in rare and widespread pines. Molecular Ecology (2010).
- Giresi P, Buenrostro JD, Chang HY, Greenleaf WJ. Transposition of Native Chromatin for Personal Epigenomics (2013).
- Bustamante CD, Carpenter ML, Buenrostro JD, Greenleaf WJ. Enrichment of DNA Sequencing Libraries from Samples Containing Small Amounts of Target DNA (2013).
- Myllykangas S, Buenrostro JD, Ji HP. Direct Capture, Amplification and Sequencing of Target DNA Using Immobilized Primers (2010).