Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

Christopher S. Smillie; Moshe Biton; Jose Ordovas-Montanes; Ken M. Sullivan; Grace Burgin; Daniel B. Graham; Rebecca H. Herbst; Noga Rogel; Michel Slyper; Julia Waldman; Malika Sud; Elizabeth Andrews; Gabriella Velonias; Adam L. Haber; Karthik Jagadeesh; Sanja Vickovic; Junmei Yao; Christine Stevens; Danielle Dionne; Lan T. Nguyen; Alexandra-Chloe Villani; Matan Hofree; Elizabeth A. Creasey; Hailiang Huang; Orit Rozenblatt-Rosen; John J. Garber; Hamed Khalili; A. Nicole Desch; Mark J. Daly; Ashwin N. Ananthakrishnan; Alex K. Shalek; Ramnik J. Xavier; Aviv Regev

doi:10.1016/j.cell.2019.06.029

Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

Christopher S. Smillie, Moshe Biton, Jose Ordovas-Montanes, Ken M. Sullivan, Grace Burgin, Daniel B. Graham, Rebecca H. Herbst, Noga Rogel, Michel Slyper, Julia Waldman, Malika Sud, Elizabeth Andrews, Gabriella Velonias, Adam L. Haber, Karthik Jagadeesh, Sanja Vickovic, Junmei Yao, Christine Stevens, Danielle Dionne, Lan T. NguyenAlexandra-Chloe Villani, Matan Hofree, Elizabeth A. Creasey, Hailiang Huang, Orit Rozenblatt-Rosen, John J. Garber, Hamed Khalili, A. Nicole Desch, Mark J. Daly, Ashwin N. Ananthakrishnan, Alex K. Shalek, Ramnik J. Xavier, Aviv Regev

Research output: Contribution to journal › Article › peer-review

Abstract

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4(+) enterocytes, microfold-like cells, and IL13RA2(+)IL11(+) inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and coregulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.

Original language	English
Pages (from-to)	714-730
Number of pages	17
Journal	Cell
Volume	178
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2019.06.029
State	Published - 25 Jul 2019
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.cell.2019.06.029

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Smillie, C. S., Biton, M., Ordovas-Montanes, J., Sullivan, K. M., Burgin, G., Graham, D. B., Herbst, R. H., Rogel, N., Slyper, M., Waldman, J., Sud, M., Andrews, E., Velonias, G., Haber, A. L., Jagadeesh, K., Vickovic, S., Yao, J., Stevens, C., Dionne, D., ... Regev, A. (2019). Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell, 178(3), 714-730. https://doi.org/10.1016/j.cell.2019.06.029

@article{088e02b8daa44e8187d459dc926c1cb3,

title = "Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis",

abstract = "Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4(+) enterocytes, microfold-like cells, and IL13RA2(+)IL11(+) inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and coregulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.",

author = "Smillie, {Christopher S.} and Moshe Biton and Jose Ordovas-Montanes and Sullivan, {Ken M.} and Grace Burgin and Graham, {Daniel B.} and Herbst, {Rebecca H.} and Noga Rogel and Michel Slyper and Julia Waldman and Malika Sud and Elizabeth Andrews and Gabriella Velonias and Haber, {Adam L.} and Karthik Jagadeesh and Sanja Vickovic and Junmei Yao and Christine Stevens and Danielle Dionne and Nguyen, {Lan T.} and Alexandra-Chloe Villani and Matan Hofree and Creasey, {Elizabeth A.} and Hailiang Huang and Orit Rozenblatt-Rosen and Garber, {John J.} and Hamed Khalili and Desch, {A. Nicole} and Daly, {Mark J.} and Ananthakrishnan, {Ashwin N.} and Shalek, {Alex K.} and Xavier, {Ramnik J.} and Aviv Regev",

note = "We thank all consenting participants of this study, the clinical staff at Massachusetts General Hospital, Leslie Gaffney and Anna Hupalowska for help with figures, Tim Tickle for help with the Single Cell Portal, Vijay Yajnik, Frank Colizzo, and Abdifatah Omer. M.B. was supported by a postdoctoral fellowship from the Human Frontiers Science Program. J.O.-M. is an HHMI Damon Runyon Cancer Research Foundation Fellow (DRG-2274-16). Work was supported by the Klarman Cell Observatory (to A.R. and R.J.X.); HHMI (to A.R.); the Manton Foundation (to A.R. and R.X.); Broadnext10 (to A.R. and R.J.X.); DK043351, DK114784, DK117263, the Helmsley Charitable Trust, and the Crohn's and Colitis Foundation (to R.J.X.); a Sloan Fellowship in Chemistry (to A.K.S.); the Searle Scholars Program (to A.K.S.); the Beckman Young Investigator Program (to A.K.S.); and NIH 5U24AI118672 (to A.R. and A.K.S.). This publication is part of the Human Cell Atlas. Author Contributions M.B. and J.O.-M. designed and performed experiments with A.K.S., R.J.X., A.N.A., A.R., G.B., N.R., M. Slyper, J.W., M. Sud, S.V., J.Y., E.A.C., and A.N.D. C.S.S. designed and performed computational analyses with A.R., R.J.X., D.B.G., R.H.H., A.L.H., K.J., A.-C.V., M.H., H.H., M.B., J.O.-M., and M.J.D. K.M.S., E.A., and G.V. performed clinical work with C.S., J.J.G., H.K., A.N.A., and R.J.X. D.D., L.T.N., and O.R.-R. assisted with scRNA-seq. C.S.S., M.B., J.O.-M., A.K.S., R.J.X., and A.R. wrote the manuscript with input from all authors.",

year = "2019",

month = jul,

day = "25",

doi = "10.1016/j.cell.2019.06.029",

language = "الإنجليزيّة",

volume = "178",

pages = "714--730",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "3",

}

Smillie, CS, Biton, M, Ordovas-Montanes, J, Sullivan, KM, Burgin, G, Graham, DB, Herbst, RH, Rogel, N, Slyper, M, Waldman, J, Sud, M, Andrews, E, Velonias, G, Haber, AL, Jagadeesh, K, Vickovic, S, Yao, J, Stevens, C, Dionne, D, Nguyen, LT, Villani, A-C, Hofree, M, Creasey, EA, Huang, H, Rozenblatt-Rosen, O, Garber, JJ, Khalili, H, Desch, AN, Daly, MJ, Ananthakrishnan, AN, Shalek, AK, Xavier, RJ & Regev, A 2019, 'Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis', Cell, vol. 178, no. 3, pp. 714-730. https://doi.org/10.1016/j.cell.2019.06.029

TY - JOUR

T1 - Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

AU - Smillie, Christopher S.

AU - Biton, Moshe

AU - Ordovas-Montanes, Jose

AU - Sullivan, Ken M.

AU - Burgin, Grace

AU - Graham, Daniel B.

AU - Herbst, Rebecca H.

AU - Rogel, Noga

AU - Slyper, Michel

AU - Waldman, Julia

AU - Sud, Malika

AU - Andrews, Elizabeth

AU - Velonias, Gabriella

AU - Haber, Adam L.

AU - Jagadeesh, Karthik

AU - Vickovic, Sanja

AU - Yao, Junmei

AU - Stevens, Christine

AU - Dionne, Danielle

AU - Nguyen, Lan T.

AU - Villani, Alexandra-Chloe

AU - Hofree, Matan

AU - Creasey, Elizabeth A.

AU - Huang, Hailiang

AU - Rozenblatt-Rosen, Orit

AU - Garber, John J.

AU - Khalili, Hamed

AU - Desch, A. Nicole

AU - Daly, Mark J.

AU - Ananthakrishnan, Ashwin N.

AU - Shalek, Alex K.

AU - Xavier, Ramnik J.

AU - Regev, Aviv

N1 - We thank all consenting participants of this study, the clinical staff at Massachusetts General Hospital, Leslie Gaffney and Anna Hupalowska for help with figures, Tim Tickle for help with the Single Cell Portal, Vijay Yajnik, Frank Colizzo, and Abdifatah Omer. M.B. was supported by a postdoctoral fellowship from the Human Frontiers Science Program. J.O.-M. is an HHMI Damon Runyon Cancer Research Foundation Fellow (DRG-2274-16). Work was supported by the Klarman Cell Observatory (to A.R. and R.J.X.); HHMI (to A.R.); the Manton Foundation (to A.R. and R.X.); Broadnext10 (to A.R. and R.J.X.); DK043351, DK114784, DK117263, the Helmsley Charitable Trust, and the Crohn's and Colitis Foundation (to R.J.X.); a Sloan Fellowship in Chemistry (to A.K.S.); the Searle Scholars Program (to A.K.S.); the Beckman Young Investigator Program (to A.K.S.); and NIH 5U24AI118672 (to A.R. and A.K.S.). This publication is part of the Human Cell Atlas. Author Contributions M.B. and J.O.-M. designed and performed experiments with A.K.S., R.J.X., A.N.A., A.R., G.B., N.R., M. Slyper, J.W., M. Sud, S.V., J.Y., E.A.C., and A.N.D. C.S.S. designed and performed computational analyses with A.R., R.J.X., D.B.G., R.H.H., A.L.H., K.J., A.-C.V., M.H., H.H., M.B., J.O.-M., and M.J.D. K.M.S., E.A., and G.V. performed clinical work with C.S., J.J.G., H.K., A.N.A., and R.J.X. D.D., L.T.N., and O.R.-R. assisted with scRNA-seq. C.S.S., M.B., J.O.-M., A.K.S., R.J.X., and A.R. wrote the manuscript with input from all authors.

PY - 2019/7/25

Y1 - 2019/7/25

N2 - Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4(+) enterocytes, microfold-like cells, and IL13RA2(+)IL11(+) inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and coregulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.

AB - Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4(+) enterocytes, microfold-like cells, and IL13RA2(+)IL11(+) inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and coregulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.

UR - http://www.scopus.com/inward/record.url?scp=85069176109&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2019.06.029

DO - 10.1016/j.cell.2019.06.029

M3 - مقالة

SN - 0092-8674

VL - 178

SP - 714

EP - 730

JO - Cell

JF - Cell

IS - 3

ER -

Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

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