Christine Cheng

Current Research

Our lab studies transcriptional regulatory network and aims to develop a comprehensive understanding of how aberrant regulatory circuits contribute to human disease. Heterogeneity in clinical tissue samples has been the major obstacle in studying human disease. Being able to perform functional genomic profiles of thousands of single cells at once enables us to dissect a heterogenous tissue sample or cell population without the need to isolate and sort for each sub populations. We utilize and develop novel massively-parallel single-cell transcriptomic and epigenetic profiling technologies based on droplet based microfluidic device to study heterogenous clinical tissue samples and blood immune cell populations in patients.

Complex behaviors in multicellular organisms result from the cooperation of functionally specialized cell types. However, deconvolution of cell mixtures into distinct subpopulations can be challenging due to a lack of, or promiscuous, expression of specific cell surface markers. In one of the project, we performed single-cell epigenetic assay (ATAC-seq) over 2000 single cells to discover de novo cell state classifications in resting and pathogen-stimulated DCs. We find significant variation in chromatin accessibility, which can be systematically linked to the activity of specific trans-factors and cis-elements in individual cells. Integrative analysis with massively-parallel single-cell RNA-seq over 35,000 single cells, multi-parameter flow cytometry, and CRISPR editing knockout studies allowed for the validation of de novo-defined developmental cell states with functionally distinct responses to identical pathogen stimuli. This study highlights principles of cell-type specific networks underlying complex cellular behaviors – and the ability to interrogate these states ‘bottom-up’ using single cell epigenomic profiling.

In another project, we utilized epigenetic variability between individual humans as a perturbation tool to dissect transcriptional regulatory network. The vast majority of genetic variants associated with complex human traits map to non-coding and gene regulatory regions, but little is understood about how such genetic variants modulate gene regulation in health and disease. Utilizing a recently available assay, Assay for Transposase-Accessible Chromatin (ATAC-seq) for fast and sensitive epigenomic profiling of open chromatin, we performed ATAC-seq and RNA-seq in activated human CD4+ T cells from 100 healthy individuals to identify ATAC-QTLs: genetic variants associated with variability in chromatin accessibility. We found that ATAC-QTLs are widespread, disrupt binding sites for known transcription factors important for CD4+ T cell differentiation and activation, overlap and mediate expression QTLs from the same cells and are enriched for SNPs associated with autoimmune diseases. Our results provide insights into how genetic variants modulate chromatin state and gene expression in primary immune cells that play a key role in many human diseases.

Current projects focus on applying massively-parallel single-cell transcriptomic and epigenetic profiling in Type 2 diabetes, substance addiction and Alzheimer disease patient samples, with the goal of finding diagnostic markers and therapeutic targets.

Selected Publications

• Cheng CS*, Gate RE*, Aiden AP, Siba A, Tabaka M, Lituiev D, Machol I, Subramaniam M, Shamim M, Hougen KL, Wortman I, Huan SC, Durand NC, Feng T, De Jager PL, Chang HY, Aiden EL, Benoist C, Beer MA, Ye CJ§, Regev A§ (2017) Genetic determinants of chromatin accessibility and gene regulation in T cell activation across human individuals. Accepted for publication in Nature Genetics preprint. (* Equal contribution; § corresponding authors)
• 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 (2017) PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes. Genes Dev. 31(10):973-989. PMID: 28607179
• Cheng CS*, Behar MS*, Suryawanish GW, Feldman KE, Spreafico R, Hoffmann A (2017) Iterative modeling reveals evidence of sequential transcriptional control mechanisms. Cell Systems PII: S2405-4712(17)30012-1 (* Equal contribution)
• Sanjana NE, Wright J, Zheng K, Shalem O, Fontanillas P, Joung J, Cheng CS, Regev A, Zhang F (2016) High-throughput dissection of the human noncoding genome. Science 353(6307): 1545-1549. PMID: 27708104
• Cheng CS, Rai K, Garber M, Hollinger A, Robbins D, Anderson S, Macbeth A, Tzou A, Carneiro MO, Raychowdhury R, Russ C, Hacohen N, Gershenwald JE, Lennon N, Nusbaum C, Chin L, Regev A, Amit I (2013) Semiconductor-based DNA sequencing of histone modification states. Nature Communications. 4:2672. PMCID: PMC3917140
• Garber M, Yosef N, Goren A, Raychowdhury R, Thielke A, Guttman M, Robinson J, Minie B, Chevrier N, Itzhaki Z, Blecher-Gonen R, Bornstein C, Amann-Zalcenstein D, Weiner A, Friedrich D, Meldrim J, Ram O, Cheng C, Gnirke A, Fisher S, Friedman N, Wong B, Bernstein BE, Nusbaum C, Hacohen N, Regev A, Amit I (2012) A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals. Mol Cell 47(5):810-22. PMCID: PMC3873101
• Cheng CS, Feldman KE, Lee J, Verma S, Huang DB, Huynh K, Chang M, Ponomarenko JC, Sun SC, Benedict CA, Ghosh G, Hoffmann A (2011) The specificity of innate immune responses is enforced by repression of interferon response elements by NFkB p50. Science Signaling 4(161):ra11. PMCID: PMC3096068
• Cheng CS, Johnson TL, Hoffmann A (2008) Epigenetic control: slow and global, nimble and local. Genes and Development 22(9):1110-4. PMCID: PMC2732403