Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells

Ullah Ubaid Ullah; Syed Bilal Ahmad Andrabi; Subhash Kumar Tripathi; Obaiah Dirasantha; Kartiek Kanduri; Sini Rautio; Catharina C. Gross; Sari Lehtimäki; Kanchan Bala; Johanna Tuomisto; Urvashi Bhatia; Deepankar Chakroborty; Laura L. Elo; Harri Lähdesmäki; Heinz Wiendl; Omid Rasool; Riitta Lahesmaa

doi:10.1016/j.celrep.2018.01.070

Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells

Ullah Ubaid Ullah
, Syed Bilal Ahmad Andrabi
, Subhash Kumar Tripathi
, Obaiah Dirasantha
, Kartiek Kanduri
, Sini Rautio
, Catharina C. Gross
, Sari Lehtimäki
, Kanchan Bala
, Johanna Tuomisto
, Urvashi Bhatia
, Deepankar Chakroborty
, Laura L. Elo
, Harri Lähdesmäki
, Heinz Wiendl
, Omid Rasool
, Riitta Lahesmaa^*

^*Tämän työn vastaava kirjoittaja

Åbo Akademi University
University of Münster
Hospital District of Helsinki and Uusimaa

Tutkimustuotos: Lehtiartikkeli › Article › Scientific › vertaisarvioitu

44 Viittaukset (Web of Science)

296 Lataukset (Pure)

Abstrakti

Regulatory T (Treg) cells are critical in regulating the immune response. In vitro induced Treg (iTreg) cells have significant potential in clinical medicine. However, applying iTreg cells as therapeutics is complicated by the poor stability of human iTreg cells and their variable suppressive activity. Therefore, it is important to understand the molecular mechanisms of human iTreg cell specification. We identified hypermethylated in cancer 1 (HIC1) as a transcription factor upregulated early during the differentiation of human iTreg cells. Although FOXP3 expression was unaffected, HIC1 deficiency led to a considerable loss of suppression by iTreg cells with a concomitant increase in the expression of effector T cell associated genes. SNPs linked to several immune-mediated disorders were enriched around HIC1 binding sites, and in vitro binding assays indicated that these SNPs may alter the binding of HIC1. Our results suggest that HIC1 is an important contributor to iTreg cell development and function. Ullah et al. find that HIC1 is induced during human iTreg cell differentiation. HIC1 binds to and regulates the expression of key genes during iTreg differentiation. Several autoimmune-disease-associated SNPs are enriched near HIC1 ChIP-seq peaks.

Alkuperäiskieli	Englanti
Sivut	2094-2106
Sivumäärä	13
Julkaisu	Cell Reports
Vuosikerta	22
Numero	8
DOI - pysyväislinkit	https://doi.org/10.1016/j.celrep.2018.01.070
Tila	Julkaistu - 20 helmik. 2018
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

This study was supported by Academy of Finland (AoF) grants 256355 , 258313 , 259942 , 292482 , and 294337 ; by the AoF Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012–2017 grant 250114 ; AoF Terva grant 314444 ; and by grants from the Sigrid Jusélius Foundation (SJF), the Paulo Foundation , and the Finnish Cancer Foundation . This work was supported by the AOF and the German Research Foundation (DFG; WI1722/12-1 ) Immunology Initiative “Systems Biology Approach to Molecular Mechanisms of Human TGF-β Induced iTreg Cell Differentiation and the Role of iTreg in Multiple Sclerosis” to R.L., H.L., and H.W., as well as DFG Collaborative Research Centre CRC/SFB128 “Initiating/Effector versus Regulatory Mechanisms in Multiple Sclerosis – Progress towards Tackling the Disease,” project A09, to H.W. and C.C.G. U.B. is funded by the Cluster of Excellence Cells in Motion (CiM). L.L.E. has received grants from the European Research Council (ERC; grant 677943 ), the European Union ’s Horizon 2020 research and innovation program (grant 675395 ), the AoF (grants 296801 and 304995 ), the Juvenile Diabetes Research Foundation (JDRF; grant 2-2013-32 ), the Finnish Funding Agency for Innovation (TEKES; grant 1877/31/2016 ), and SJF . We thank all the volunteer blood donors and personnel of Turku University Hospital, Department of Obstetrics and Gynecology, Maternity Ward Hospital District of Southwest Finland for the cord blood collection. Lysates from mouse Th0/iTreg cells were kindly provided by Tanja Buchacher and Mohd Moin Khan. We acknowledge Marjo Hakkarinen for technical help with the experiments and Bridget Palmer for critical reading of the manuscript. This study was supported by the Finnish Functional Genomics Centre , the University of Turku , Åbo Akademi University , and Biocenter Finland . C.C.G. has received speaking honoraria and travel expenses for attending meeting for Biogen, Genzyme, Novartis Pharma, and Bayer Health Care. Her work is funded by the German Ministry for Education and Research (BMBF; 01GI1603A ) and the German Research Foundation (DFG; GR3946/3-1 and SFB128 A09 ). H.W. receives honoraria for acting as a member of scientific advisory boards and as consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma, and Sanofi-Genzyme and speaking honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma, Sanofi-Genzyme, Teva, and WebMD Global. H.W. acts as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. Research by H.W. is funded by the BMBF ( 01FI1601E , 01GI1603A , and O1GI1603D ), DFG ( SFB128 A09 , A10 , Z02 , V and SFB1009 A03 ), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen, GlaxoSmithKline, Roche Pharma, and Sanofi-Genzyme. All other authors have no financial interest related to this work.

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10.1016/j.celrep.2018.01.070

1-s2.0-S2211124718301190-mainFinal published version, 3,63 MBLisenssi: CC BY-NC-ND

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Ubaid Ullah, U., Andrabi, S. B. A., Tripathi, S. K., Dirasantha, O., Kanduri, K., Rautio, S., Gross, C. C., Lehtimäki, S., Bala, K., Tuomisto, J., Bhatia, U., Chakroborty, D., Elo, L. L., Lähdesmäki, H., Wiendl, H., Rasool, O., & Lahesmaa, R. (2018). Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells. Cell Reports, 22(8), 2094-2106. https://doi.org/10.1016/j.celrep.2018.01.070

@article{d946adda93004a3c88c908895ecc3d6f,

title = "Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells",

abstract = "Regulatory T (Treg) cells are critical in regulating the immune response. In vitro induced Treg (iTreg) cells have significant potential in clinical medicine. However, applying iTreg cells as therapeutics is complicated by the poor stability of human iTreg cells and their variable suppressive activity. Therefore, it is important to understand the molecular mechanisms of human iTreg cell specification. We identified hypermethylated in cancer 1 (HIC1) as a transcription factor upregulated early during the differentiation of human iTreg cells. Although FOXP3 expression was unaffected, HIC1 deficiency led to a considerable loss of suppression by iTreg cells with a concomitant increase in the expression of effector T cell associated genes. SNPs linked to several immune-mediated disorders were enriched around HIC1 binding sites, and in vitro binding assays indicated that these SNPs may alter the binding of HIC1. Our results suggest that HIC1 is an important contributor to iTreg cell development and function. Ullah et al. find that HIC1 is induced during human iTreg cell differentiation. HIC1 binds to and regulates the expression of key genes during iTreg differentiation. Several autoimmune-disease-associated SNPs are enriched near HIC1 ChIP-seq peaks.",

keywords = "ChIP-seq, expression kinetics, FOXP3, HIC1, iTreg, regulatory SNP, RNA-seq, suppression, T cells, transcriptional regulation",

author = "\{Ubaid Ullah\}, Ullah and Andrabi, \{Syed Bilal Ahmad\} and Tripathi, \{Subhash Kumar\} and Obaiah Dirasantha and Kartiek Kanduri and Sini Rautio and Gross, \{Catharina C.\} and Sari Lehtim{\"a}ki and Kanchan Bala and Johanna Tuomisto and Urvashi Bhatia and Deepankar Chakroborty and Elo, \{Laura L.\} and Harri L{\"a}hdesm{\"a}ki and Heinz Wiendl and Omid Rasool and Riitta Lahesmaa",

year = "2018",

month = feb,

day = "20",

doi = "10.1016/j.celrep.2018.01.070",

language = "English",

volume = "22",

pages = "2094--2106",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "8",

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Ubaid Ullah, U, Andrabi, SBA, Tripathi, SK, Dirasantha, O, Kanduri, K, Rautio, S, Gross, CC, Lehtimäki, S, Bala, K, Tuomisto, J, Bhatia, U, Chakroborty, D, Elo, LL, Lähdesmäki, H, Wiendl, H, Rasool, O & Lahesmaa, R 2018, 'Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells', Cell Reports, Vuosikerta 22, Nro 8, Sivut 2094-2106. https://doi.org/10.1016/j.celrep.2018.01.070

TY - JOUR

T1 - Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells

AU - Ubaid Ullah, Ullah

AU - Andrabi, Syed Bilal Ahmad

AU - Tripathi, Subhash Kumar

AU - Dirasantha, Obaiah

AU - Kanduri, Kartiek

AU - Rautio, Sini

AU - Gross, Catharina C.

AU - Lehtimäki, Sari

AU - Bala, Kanchan

AU - Tuomisto, Johanna

AU - Bhatia, Urvashi

AU - Chakroborty, Deepankar

AU - Elo, Laura L.

AU - Lähdesmäki, Harri

AU - Wiendl, Heinz

AU - Rasool, Omid

AU - Lahesmaa, Riitta

PY - 2018/2/20

Y1 - 2018/2/20

N2 - Regulatory T (Treg) cells are critical in regulating the immune response. In vitro induced Treg (iTreg) cells have significant potential in clinical medicine. However, applying iTreg cells as therapeutics is complicated by the poor stability of human iTreg cells and their variable suppressive activity. Therefore, it is important to understand the molecular mechanisms of human iTreg cell specification. We identified hypermethylated in cancer 1 (HIC1) as a transcription factor upregulated early during the differentiation of human iTreg cells. Although FOXP3 expression was unaffected, HIC1 deficiency led to a considerable loss of suppression by iTreg cells with a concomitant increase in the expression of effector T cell associated genes. SNPs linked to several immune-mediated disorders were enriched around HIC1 binding sites, and in vitro binding assays indicated that these SNPs may alter the binding of HIC1. Our results suggest that HIC1 is an important contributor to iTreg cell development and function. Ullah et al. find that HIC1 is induced during human iTreg cell differentiation. HIC1 binds to and regulates the expression of key genes during iTreg differentiation. Several autoimmune-disease-associated SNPs are enriched near HIC1 ChIP-seq peaks.

AB - Regulatory T (Treg) cells are critical in regulating the immune response. In vitro induced Treg (iTreg) cells have significant potential in clinical medicine. However, applying iTreg cells as therapeutics is complicated by the poor stability of human iTreg cells and their variable suppressive activity. Therefore, it is important to understand the molecular mechanisms of human iTreg cell specification. We identified hypermethylated in cancer 1 (HIC1) as a transcription factor upregulated early during the differentiation of human iTreg cells. Although FOXP3 expression was unaffected, HIC1 deficiency led to a considerable loss of suppression by iTreg cells with a concomitant increase in the expression of effector T cell associated genes. SNPs linked to several immune-mediated disorders were enriched around HIC1 binding sites, and in vitro binding assays indicated that these SNPs may alter the binding of HIC1. Our results suggest that HIC1 is an important contributor to iTreg cell development and function. Ullah et al. find that HIC1 is induced during human iTreg cell differentiation. HIC1 binds to and regulates the expression of key genes during iTreg differentiation. Several autoimmune-disease-associated SNPs are enriched near HIC1 ChIP-seq peaks.

KW - ChIP-seq

KW - expression kinetics

KW - FOXP3

KW - HIC1

KW - iTreg

KW - regulatory SNP

KW - RNA-seq

KW - suppression

KW - T cells

KW - transcriptional regulation

UR - https://www.scopus.com/pages/publications/85042194008

U2 - 10.1016/j.celrep.2018.01.070

DO - 10.1016/j.celrep.2018.01.070

M3 - Article

AN - SCOPUS:85042194008

SN - 2211-1247

VL - 22

SP - 2094

EP - 2106

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells

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