, Alexa Fluor 647-conjugated anti-Rat IgG secondary antibody (A21247, Invitrogen, 1:1000 dilution) or Alexa Fluor 647-conjugated anti-chicken IgY secondary antibody, 4°C. Alexa Fluor 488-conjugated anti-rabbit IgG secondary antibody (A21206, Invitrogen, 1:1000 dilution), vol.1, p.1000, 21449.

, Briefly, chromatin DNA was obtained from colon tissue or cultured organoids after fixation with formaldehyde and fragmented using micrococcal nuclease and sonication to generate lengths of~150-900 bp. Digested chromatin was then incubated with control IgG (2729, Cell Signaling) or anti-acetyl-histone H3 Ab (06-599, EMD Millipore, 1:150 dilution) and precipitated using protein G agarose beads (9007, Cell Signaling). ChIP DNA was purified and subjected to qPCR using iTaq Universal SYBR Green Supermix, Chromatin immunoprecipitation (ChIP). ChIP assays were performed using the SimpleChIP Plus Enzymatic Chromatin IP kit (9004 S, Cell Signaling), 1725124.

R. and 5. ,

, Gy) and were injected with Erdr1 (6 ?g/mice) daily on days 0, 1, and 2. At day 3 post radiation, intestinal tissue was collected and stained with Ki-67 and EGFP (as a surrogate of Lgr5 expression). For TUNEL assays, paraffin embedded tissue sections were stained using the Click-iT TUNEL Assay for, For radiation-induced injury, mice received whole body X-ray radiation

, Biomedicals; molecular weight: 36,000-50,000) in the drinking water for 5 days and then switched to normal drinking water. Mice were monitored daily for signs of disease with score of 0-4 assigned for weight loss, stool consistency, and presence of blood in stool. The individual scores were added and the average score was DAI. For anti-Erdr1 Ab treatment, mice were injected (i, DSS model of colonic damage. Mice were treated with 3% (wt/vol) DSS (MP

. Histology, Colons were fixed with 10% formalin and embedded by paraffin. Tissue was cut into 5 ?m sections and stained with hematoxylin/eosin. The degree of inflammation and epithelial damage was scored with average of two parameters include immune cell infiltration (0-3) and intestinal architecture, pp.0-3

, Total RNA was isolated from cells and tissues using a Qiagen RNeasy Mini Kit and QIAcube with on column DNase digestion. cDNA was generated using the Hight-Capacity cDNA Reverse Transcriptional Kit (Applied Biosystems). qPCR was performed with SYBR Green on a StepOnePlus real-time PCR system (Applied Biosystems) and gene expression was normalized to Gapdh, RNA isolation and qPCR, pp.5-8

R. and 5. Atactgag-3?,

(. Ascl2 and 5. ,

R. and 5. Tttggt, 3?) Smoc2 (F, pp.5-8

R. , 5. Cacat-3?)-olfm4, (. , and 5. ,

R. and 5. Tgaaaggatgg-3?,

(. Axin2 and 5. ,

R. and 5. Tactgc-3?,

(. Myc and 5. ,

R. ,

R. and 5. Gtagctt-3?,

(. Hes1 and 5. ,

R. and 5. Tgaaaag-3?,

(. Ctgf and 5. ,

R. and 5. Ccgct-3?,

(. Gapdh and 5. ,

R. and 5. ,

R. E. Ley, C. A. Lozupone, M. Hamady, R. Knight, and J. I. Gordon, Worlds within worlds: evolution of the vertebrate gut microbiota, Nat. Rev. Microbiol, vol.6, pp.776-788, 2008.

L. V. Hooper, Epithelial cell contributions to intestinal immunity, Adv. Immunol, vol.126, pp.129-172, 2015.

L. V. Hooper, D. R. Littman, and A. J. Macpherson, Interactions between the microbiota and the immune system, Science, vol.336, pp.1268-1273, 2012.

K. Honda and D. R. Littman, The microbiota in adaptive immune homeostasis and disease, Nature, vol.535, pp.75-84, 2016.

M. G. Dominguez-bello, F. Godoy-vitorino, R. Knight, and M. J. Blaser, Role of the microbiome in human development, Gut, vol.68, pp.1108-1114, 2019.

R. Knight, The microbiome and human biology, Annu. Rev. Genomics Hum. Genet, vol.18, pp.65-86, 2017.

J. A. Gilbert, Microbiome-wide association studies link dynamic microbial consortia to disease, Nature, vol.535, pp.94-103, 2016.

T. Gensollen, S. S. Iyer, D. L. Kasper, and R. S. Blumberg, How colonization by microbiota in early life shapes the immune system, Science, vol.352, pp.539-544, 2016.

L. Jostins, Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Nature, vol.491, pp.119-124, 2012.

M. J. Ege, Exposure to environmental microorganisms and childhood asthma, N. Engl. J. Med, vol.364, pp.701-709, 2011.

P. Gholizadeh, Microbial balance in the intestinal microbiota and its association with diabetes, obesity and allergic disease, Micro. Pathog, vol.127, pp.48-55, 2019.

J. L. Round and S. K. Mazmanian, The gut microbiota shapes intestinal immune responses during health and disease, Nat. Rev. Immunol, vol.9, pp.313-323, 2009.

A. N. Skelly, Y. Sato, S. Kearney, and K. Honda, Mining the microbiota for microbial and metabolite-based immunotherapies, Nat. Rev. Immunol, vol.19, pp.305-323, 2019.

M. Gomez-de-aguero, The maternal microbiota drives early postnatal innate immune development, Science, vol.351, pp.1296-1302, 2016.

A. J. Macpherson, M. G. De-aguero, and S. C. Ganal-vonarburg, How nutrition and the maternal microbiota shape the neonatal immune system, Nat. Rev. Immunol, vol.17, pp.508-517, 2017.

S. Tamburini, N. Shen, H. C. Wu, and J. C. Clemente, The microbiome in early life: implications for health outcomes, Nat. Med, vol.22, pp.713-722, 2016.

L. M. Kato, S. Kawamoto, M. Maruya, and S. Fagarasan, The role of the adaptive immune system in regulation of gut microbiota, Immunol. Rev, vol.260, pp.67-75, 2014.

M. Levy, C. A. Thaiss, and E. Elinav, Metabolites: messengers between the microbiota and the immune system, Genes Dev, vol.30, pp.1589-1597, 2016.

A. M. Marchiando, W. V. Graham, and J. R. Turner, Epithelial barriers in homeostasis and disease, Annu. Rev. Pathol, vol.5, pp.119-144, 2010.

J. Beumer and H. Clevers, Regulation and plasticity of intestinal stem cells during homeostasis and regeneration, Development, vol.143, pp.3639-3649, 2016.

Y. K. Houh, K. E. Kim, H. J. Park, and D. Cho, Roles of erythroid differentiation regulator 1 (Erdr1) on inflammatory skin diseases, Int. J. Mol. Sci, vol.17, p.2059, 2016.

A. M. Weis, R. Soto, and J. L. Round, Commensal regulation of T cell survival through Erdr1, Gut Microbes, vol.9, pp.458-464, 2018.

R. Soto, Microbiota promotes systemic T-cell survival through suppression of an apoptotic factor, Proc. Natl Acad. Sci. USA, vol.114, pp.5497-5502, 2017.

T. Alenghat and D. Artis, Epigenomic regulation of host-microbiota interactions, Trends Immunol, vol.35, pp.518-525, 2014.

P. Dormer, E. Spitzer, M. Frankenberger, and E. Kremmer, Erythroid differentiation regulator (EDR), a novel, highly conserved factor I. Induction of haemoglobin synthesis in erythroleukaemic cells, Cytokine, vol.26, pp.231-242, 2004.

J. Lee, M. K. Jung, H. J. Park, K. E. Kim, and D. Cho, Erdr1 Suppresses murine melanoma growth via regulation of apoptosis, Int. J. Mol. Sci, vol.17, p.107, 2016.

R. L. Mango, C-C chemokine receptor 5 on pulmonary mesenchymal cells promotes experimental metastasis via the induction of erythroid differentiation regulator 1, Mol. Cancer Res, vol.12, pp.274-282, 2014.

F. Wang, RNAscope: a novel in situ RNA analysis platform for formalinfixed, paraffin-embedded tissues, J. Mol. Diagn, vol.14, pp.22-29, 2012.

N. Barker, Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration, Nat. Rev. Mol. Cell Biol, vol.15, pp.19-33, 2014.

S. Yu, Paneth cell multipotency induced by notch activation following injury, Cell Stem Cell, vol.23, pp.46-59, 2018.

H. R. Lee, ERDR1 enhances human NK cell cytotoxicity through an actin-regulated degranulation-dependent pathway, Cell Immunol, vol.292, pp.78-84, 2014.

T. Sato, Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche, Nature, vol.459, pp.262-265, 2009.

H. Clevers, K. M. Loh, and R. Nusse, Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control, Science, vol.346, p.1248012, 2014.

H. Gehart and H. Clevers, Tales from the crypt: new insights into intestinal stem cells, Nat. Rev. Gastroenterol. Hepatol, vol.16, pp.19-34, 2019.

J. H. Van-es, A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic self-renewal, Mol. Cell Biol, vol.32, pp.1918-1927, 2012.

H. F. Farin, E. J. Van, and H. Clevers, Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells, Gastroenterology, vol.143, p.1517, 2012.

K. L. Vandussen, Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells, Development, vol.139, pp.488-497, 2012.

A. Gregorieff, Y. Liu, M. R. Inanlou, Y. Khomchuk, and J. L. Wrana, Yapdependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer, Nature, vol.526, pp.715-718, 2015.

H. N. Suh, Quiescence exit of Tert(+) stem cells by Wnt/beta-Catenin is indispensable for intestinal regeneration, Cell Rep, vol.21, pp.2571-2584, 2017.

C. Metcalfe, N. M. Kljavin, R. Ybarra, and F. J. De-sauvage, Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration, Cell Stem Cell, vol.14, pp.149-159, 2014.

E. D. Bankaitis, A. Ha, C. J. Kuo, and S. T. Magness, Reserve stem cells in intestinal homeostasis and injury, Gastroenterology, vol.155, pp.1348-1361, 2018.

P. Dormer, E. Spitzer, and W. Moller, EDR is a stress-related survival factor from stroma and other tissues acting on early haematopoietic progenitors (E-Mix), Cytokine, vol.27, pp.47-57, 2004.

V. Woo and T. Alenghat, Host-microbiota interactions: epigenomic regulation, Curr. Opin. Immunol, vol.44, pp.52-60, 2017.

R. Fellows, Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases, Nat. Commun, vol.9, p.105, 2018.
URL : https://hal.archives-ouvertes.fr/hal-01759208

N. Navabi, Epithelial histone deacetylase 3 instructs intestinal immunity by coordinating local lymphocyte activation, Cell Rep, vol.19, pp.1165-1175, 2017.

A. Harusato, Early-life microbiota exposure restricts myeloid-derived suppressor cell-driven colonic tumorigenesis, Cancer Immunol. Res, vol.7, pp.544-551, 2019.
URL : https://hal.archives-ouvertes.fr/hal-02335668

F. Yue, A comparative encyclopedia of DNA elements in the mouse genome, Nature, vol.515, pp.355-364, 2014.

C. A. Lindemans, Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration, Nature, vol.528, pp.560-564, 2015.

K. Gronke, Interleukin-22 protects intestinal stem cells against genotoxic stress, Nature, vol.566, pp.249-253, 2019.

T. Sato and H. Clevers, Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications, Science, vol.340, pp.1190-1194, 2013.

N. Barker, Identification of stem cells in small intestine and colon by marker gene Lgr5, Nature, vol.449, pp.1003-1007, 2007.