Noncoding deletions reveal a gene that is critical for intestinal function

Danit Oz-Levi; Tsviya Olender; Ifat Bar-Joseph; Yiwen Zhu; Dina Marek-Yagel; Iros Barozzi; Marco Osterwalder; Anna Alkelai; Elizabeth K Ruzzo; Yujun Han; Erica S M Vos; Haike Reznik-Wolf; Corina Hartman; Raanan Shamir; Batia Weiss; Rivka Shapiro; Ben Pode-Shakked; Pavlo Tatarskyy; Roni Milgrom; Michael Schvimer; Iris Barshack; Denise M Imai; Devin Coleman-Derr; Diane E Dickel; Alex S Nord; Veena Afzal; Kelly Lammerts van Bueren; Ralston M Barnes; Brian L Black; Christopher N Mayhew; Matthew F Kuhar; Amy Pitstick; Mehmet Tekman; Horia C Stanescu; James M Wells; Robert Kleta; Wouter de Laat; David B Goldstein; Elon Pras; Axel Visel; Doron Lancet; Yair Anikster; Len A Pennacchio

doi:10.1038/s41586-019-1312-2

Noncoding deletions reveal a gene that is critical for intestinal function

Danit Oz-Levi, Tsviya Olender, Ifat Bar-Joseph, Yiwen Zhu, Dina Marek-Yagel, Iros Barozzi, Marco Osterwalder, Anna Alkelai, Elizabeth K Ruzzo, Yujun Han, Erica S M Vos, Haike Reznik-Wolf, Corina Hartman, Raanan Shamir, Batia Weiss, Rivka Shapiro, Ben Pode-Shakked, Pavlo Tatarskyy, Roni Milgrom, Michael SchvimerIris Barshack, Denise M Imai, Devin Coleman-Derr, Diane E Dickel, Alex S Nord, Veena Afzal, Kelly Lammerts van Bueren, Ralston M Barnes, Brian L Black, Christopher N Mayhew, Matthew F Kuhar, Amy Pitstick, Mehmet Tekman, Horia C Stanescu, James M Wells, Robert Kleta, Wouter de Laat, David B Goldstein, Elon Pras, Axel Visel, Doron Lancet, Yair Anikster, Len A Pennacchio

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

Abstract

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

Original language	English
Pages (from-to)	107-111
Number of pages	5
Journal	Nature
Volume	571
Issue number	7763
DOIs	https://doi.org/10.1038/s41586-019-1312-2
Publication status	Published - Jul 2019

Keywords

Animals
Chromosomes, Human, Pair 16/genetics
Diarrhea/congenital
Disease Models, Animal
Enhancer Elements, Genetic/genetics
Female
Gene Expression Regulation, Developmental
Genes
Genes, Reporter
Genetic Loci/genetics
Humans
Intestines/physiology
Male
Mice
Mice, Knockout
Mice, Transgenic
Pedigree
Phenotype
Sequence Deletion/genetics
Transcriptional Activation
Transcriptome/genetics
Transgenes/genetics

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10.1038/s41586-019-1312-2

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Oz-Levi, D., Olender, T., Bar-Joseph, I., Zhu, Y., Marek-Yagel, D., Barozzi, I., Osterwalder, M., Alkelai, A., Ruzzo, E. K., Han, Y., Vos, E. S. M., Reznik-Wolf, H., Hartman, C., Shamir, R., Weiss, B., Shapiro, R., Pode-Shakked, B., Tatarskyy, P., Milgrom, R., ... Pennacchio, L. A. (2019). Noncoding deletions reveal a gene that is critical for intestinal function. Nature, 571(7763), 107-111. https://doi.org/10.1038/s41586-019-1312-2

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title = "Noncoding deletions reveal a gene that is critical for intestinal function",

abstract = "Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.",

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author = "Danit Oz-Levi and Tsviya Olender and Ifat Bar-Joseph and Yiwen Zhu and Dina Marek-Yagel and Iros Barozzi and Marco Osterwalder and Anna Alkelai and Ruzzo, {Elizabeth K} and Yujun Han and Vos, {Erica S M} and Haike Reznik-Wolf and Corina Hartman and Raanan Shamir and Batia Weiss and Rivka Shapiro and Ben Pode-Shakked and Pavlo Tatarskyy and Roni Milgrom and Michael Schvimer and Iris Barshack and Imai, {Denise M} and Devin Coleman-Derr and Dickel, {Diane E} and Nord, {Alex S} and Veena Afzal and {van Bueren}, {Kelly Lammerts} and Barnes, {Ralston M} and Black, {Brian L} and Mayhew, {Christopher N} and Kuhar, {Matthew F} and Amy Pitstick and Mehmet Tekman and Stanescu, {Horia C} and Wells, {James M} and Robert Kleta and {de Laat}, Wouter and Goldstein, {David B} and Elon Pras and Axel Visel and Doron Lancet and Yair Anikster and Pennacchio, {Len A}",

note = "Funding Information: Acknowledgements The authors thank the patients and their families for their cooperation and support. This work was supported by grants to D.L. from the SysKid EU FP7 project (241544), the Wolfson Family Charitable Trust and the Crown Human Genome Center at the Weizmann Institute of Science. A.V. and L.A.P. were supported by NHLBI grant R24HL123879 and NHGRI grants R01HG003988, U54HG006997 and UM1HG009421; J.M.W. and Y.A. were supported by the Cincinnati Children{\textquoteright}s Hospital and Sheba Medical Center{\textquoteright}s Joint Research Fund; J.M.W. and M.F.K. were supported by NIH grants 1R01DK092456 and 1U18NS080815 as well as a digestive disease center grant (P30 DK0789392); R.K. was supported by the David and Elaine Potter Charitable Foundation; B.L.B. was supported by NIH grants HL089707, HL064658 and HL136182; and I. Barozzi was funded through an Imperial College Research Fellowship. Research was conducted at the E. O. Lawrence Berkeley National Laboratory and performed under the Department of Energy contract DE-AC02-05CH11231 (University of California). iPS cell lines were generated in collaboration with the Cincinnati Children{\textquoteright}s Pluripotent Stem Cell Facility. This work was performed in partial fulfilment of the requirements for a PhD degree for D.O.-L. (Weizmann Institute of Science, Rehovot, Israel) and I.B.-J. (The Sackler Faculty of Medicine, Tel Aviv University, Israel). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2019",

month = jul,

doi = "10.1038/s41586-019-1312-2",

language = "English",

volume = "571",

pages = "107--111",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7763",

}

Oz-Levi, D, Olender, T, Bar-Joseph, I, Zhu, Y, Marek-Yagel, D, Barozzi, I, Osterwalder, M, Alkelai, A, Ruzzo, EK, Han, Y, Vos, ESM, Reznik-Wolf, H, Hartman, C, Shamir, R, Weiss, B, Shapiro, R, Pode-Shakked, B, Tatarskyy, P, Milgrom, R, Schvimer, M, Barshack, I, Imai, DM, Coleman-Derr, D, Dickel, DE, Nord, AS, Afzal, V, van Bueren, KL, Barnes, RM, Black, BL, Mayhew, CN, Kuhar, MF, Pitstick, A, Tekman, M, Stanescu, HC, Wells, JM, Kleta, R, de Laat, W, Goldstein, DB, Pras, E, Visel, A, Lancet, D, Anikster, Y & Pennacchio, LA 2019, 'Noncoding deletions reveal a gene that is critical for intestinal function', Nature, vol. 571, no. 7763, pp. 107-111. https://doi.org/10.1038/s41586-019-1312-2

TY - JOUR

T1 - Noncoding deletions reveal a gene that is critical for intestinal function

AU - Oz-Levi, Danit

AU - Olender, Tsviya

AU - Bar-Joseph, Ifat

AU - Zhu, Yiwen

AU - Marek-Yagel, Dina

AU - Barozzi, Iros

AU - Osterwalder, Marco

AU - Alkelai, Anna

AU - Ruzzo, Elizabeth K

AU - Han, Yujun

AU - Vos, Erica S M

AU - Reznik-Wolf, Haike

AU - Hartman, Corina

AU - Shamir, Raanan

AU - Weiss, Batia

AU - Shapiro, Rivka

AU - Pode-Shakked, Ben

AU - Tatarskyy, Pavlo

AU - Milgrom, Roni

AU - Schvimer, Michael

AU - Barshack, Iris

AU - Imai, Denise M

AU - Coleman-Derr, Devin

AU - Dickel, Diane E

AU - Nord, Alex S

AU - Afzal, Veena

AU - van Bueren, Kelly Lammerts

AU - Barnes, Ralston M

AU - Black, Brian L

AU - Mayhew, Christopher N

AU - Kuhar, Matthew F

AU - Pitstick, Amy

AU - Tekman, Mehmet

AU - Stanescu, Horia C

AU - Wells, James M

AU - Kleta, Robert

AU - de Laat, Wouter

AU - Goldstein, David B

AU - Pras, Elon

AU - Visel, Axel

AU - Lancet, Doron

AU - Anikster, Yair

AU - Pennacchio, Len A

N1 - Funding Information: Acknowledgements The authors thank the patients and their families for their cooperation and support. This work was supported by grants to D.L. from the SysKid EU FP7 project (241544), the Wolfson Family Charitable Trust and the Crown Human Genome Center at the Weizmann Institute of Science. A.V. and L.A.P. were supported by NHLBI grant R24HL123879 and NHGRI grants R01HG003988, U54HG006997 and UM1HG009421; J.M.W. and Y.A. were supported by the Cincinnati Children’s Hospital and Sheba Medical Center’s Joint Research Fund; J.M.W. and M.F.K. were supported by NIH grants 1R01DK092456 and 1U18NS080815 as well as a digestive disease center grant (P30 DK0789392); R.K. was supported by the David and Elaine Potter Charitable Foundation; B.L.B. was supported by NIH grants HL089707, HL064658 and HL136182; and I. Barozzi was funded through an Imperial College Research Fellowship. Research was conducted at the E. O. Lawrence Berkeley National Laboratory and performed under the Department of Energy contract DE-AC02-05CH11231 (University of California). iPS cell lines were generated in collaboration with the Cincinnati Children’s Pluripotent Stem Cell Facility. This work was performed in partial fulfilment of the requirements for a PhD degree for D.O.-L. (Weizmann Institute of Science, Rehovot, Israel) and I.B.-J. (The Sackler Faculty of Medicine, Tel Aviv University, Israel). Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2019/7

Y1 - 2019/7

N2 - Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

AB - Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

KW - Animals

KW - Chromosomes, Human, Pair 16/genetics

KW - Diarrhea/congenital

KW - Disease Models, Animal

KW - Enhancer Elements, Genetic/genetics

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Genes

KW - Genes, Reporter

KW - Genetic Loci/genetics

KW - Humans

KW - Intestines/physiology

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Pedigree

KW - Phenotype

KW - Sequence Deletion/genetics

KW - Transcriptional Activation

KW - Transcriptome/genetics

KW - Transgenes/genetics

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U2 - 10.1038/s41586-019-1312-2

DO - 10.1038/s41586-019-1312-2

M3 - Article

C2 - 31217582

SN - 0028-0836

VL - 571

SP - 107

EP - 111

JO - Nature

JF - Nature

IS - 7763

ER -

Noncoding deletions reveal a gene that is critical for intestinal function

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Keywords

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