Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity
A study investigating the mechanisms underlying lateral inhibition and lineage plasticity in the mouse small intestine crypts in vivo finds that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and this is the basis of later...
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| Veröffentlicht in: | Nature (London) 2014-02, Vol.506 (7489), p.511-515 |
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| creator | Kim, Tae-Hee Li, Fugen Ferreiro-Neira, Isabel Ho, Li-Lun Luyten, Annouck Nalapareddy, Kodandaramireddy Long, Henry Verzi, Michael Shivdasani, Ramesh A. |
| description | A study investigating the mechanisms underlying lateral inhibition and lineage plasticity in the mouse small intestine crypts
in vivo
finds that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and this is the basis of lateral inhibition.
Intestinal crypt differentiation
Intestinal crypts are the focus of intensive study, stimulated in part by the recent discovery of distinct stem-cell populations and markers. Ramesh Shivdasani and colleagues have studied mechanisms underlying lateral inhibition and lineage plasticity in mouse small intestine crypts
in vivo
. They find that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and that this is the basis of lateral inhibition.
Cells differentiate when transcription factors bind accessible
cis
-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem cells, chromatin at lineage-restricted genes becomes sequentially accessible
1
,
2
,
3
,
4
, probably by means of ‘pioneer’ transcription factor activity
5
, but tissues may use other strategies
in vivo
. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbours
6
, and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where notch signalling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages
7
,
8
,
9
. Transcript profiles in isolated LGR5
+
intestinal stem cells
10
and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNase I hypersensitivity—signifying accessible, permissive chromatin—at most of the same
cis
-elements. Enhancers acting uniquely in progenitors were well demarcated in LGR5
+
intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific transcription factor, controls lateral inhibition through delta-like notch ligand genes and a |
| doi_str_mv | 10.1038/nature12903 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4151315</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A362849929</galeid><sourcerecordid>A362849929</sourcerecordid><originalsourceid>FETCH-LOGICAL-c637t-f3f7129cb8ad68c52b36c1d5ef1a50c5ea59f9ac6326f7ee8e2bb01292d229d23</originalsourceid><addsrcrecordid>eNp1ks1v1DAQxS0EokvhxB1F9AKCgD_ixLkgLSs-KlUgQRHcLMeZ7Lry2qntVOx_j5eWsouWky3Nb55nnh9Cjwl-RTATr51KUwBCW8zuoBmpmrqsatHcRTOMqSixYPURehDjBcaYk6a6j45oVRHGWjFDP94Gr3q7KUYIaxOjuYLCuAQxGadsoVfBr1W-F5PrIVgDsbAqQcg141amM8l4VyjXFxqsLUarcqc2afMQ3RuUjfDo5jxG396_O198LM8-fzhdzM9KXbMmlQMbmjy67oTqa6E57VitSc9hIIpjzUHxdmhVhmk9NAACaNfh3EF7StuesmP05lp3nLo19BpcysPJMZi1ChvplZH7FWdWcumvZEU4YYRngWc3AsFfTnlxmX3YLqMc-ClKwjHjnBBRZ_TkH_TCTyH79JsSlWgbzP9SS2VBGjf4_K7eiso5q6mo2pa2mXp6gNKjuZS70PM9SPv8NT_TUk0xytOvX_YFX_yfnZ9_X3w6SOvgYwww3DpGsNzGSu7EKtNPdk2-Zf_kKAMvr4GYS24JYceZA3q_AN9P1yU</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1508489705</pqid></control><display><type>article</type><title>Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><source>Nature Journals Online</source><creator>Kim, Tae-Hee ; Li, Fugen ; Ferreiro-Neira, Isabel ; Ho, Li-Lun ; Luyten, Annouck ; Nalapareddy, Kodandaramireddy ; Long, Henry ; Verzi, Michael ; Shivdasani, Ramesh A.</creator><creatorcontrib>Kim, Tae-Hee ; Li, Fugen ; Ferreiro-Neira, Isabel ; Ho, Li-Lun ; Luyten, Annouck ; Nalapareddy, Kodandaramireddy ; Long, Henry ; Verzi, Michael ; Shivdasani, Ramesh A.</creatorcontrib><description>A study investigating the mechanisms underlying lateral inhibition and lineage plasticity in the mouse small intestine crypts
in vivo
finds that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and this is the basis of lateral inhibition.
Intestinal crypt differentiation
Intestinal crypts are the focus of intensive study, stimulated in part by the recent discovery of distinct stem-cell populations and markers. Ramesh Shivdasani and colleagues have studied mechanisms underlying lateral inhibition and lineage plasticity in mouse small intestine crypts
in vivo
. They find that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and that this is the basis of lateral inhibition.
Cells differentiate when transcription factors bind accessible
cis
-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem cells, chromatin at lineage-restricted genes becomes sequentially accessible
1
,
2
,
3
,
4
, probably by means of ‘pioneer’ transcription factor activity
5
, but tissues may use other strategies
in vivo
. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbours
6
, and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where notch signalling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages
7
,
8
,
9
. Transcript profiles in isolated LGR5
+
intestinal stem cells
10
and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNase I hypersensitivity—signifying accessible, permissive chromatin—at most of the same
cis
-elements. Enhancers acting uniquely in progenitors were well demarcated in LGR5
+
intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific transcription factor, controls lateral inhibition through delta-like notch ligand genes and also drives the expression of numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to the presence or absence of a key transcription factor. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted transcription factor with broadly permissive chromatin established in multipotent stem cells.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature12903</identifier><identifier>PMID: 24413398</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/100 ; 13/51 ; 38 ; 45 ; 45/15 ; 631/136/142 ; 631/532/2437 ; 64 ; 64/60 ; Animals ; Basic Helix-Loop-Helix Transcription Factors - deficiency ; Basic Helix-Loop-Helix Transcription Factors - metabolism ; Cell differentiation ; Cell Differentiation - genetics ; Cell Lineage - genetics ; Cell research ; Chromatin ; Chromatin - genetics ; Chromatin - metabolism ; Deoxyribonuclease I - metabolism ; DNA methylation ; Enhancer Elements, Genetic - genetics ; Enterocytes - cytology ; Enterocytes - metabolism ; Female ; Gene Expression Regulation ; Genetic transcription ; Genomics ; Histones - metabolism ; Humanities and Social Sciences ; Hypersensitivity ; Inhibition ; Intestine, Small - cytology ; Intestine, Small - metabolism ; letter ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; multidisciplinary ; Physiological aspects ; Plasticity ; Receptors, Notch - metabolism ; Rodents ; Science ; Stem cells ; Stem Cells - cytology ; Stem Cells - metabolism ; Transcription factors ; Transcription, Genetic</subject><ispartof>Nature (London), 2014-02, Vol.506 (7489), p.511-515</ispartof><rights>Springer Nature Limited 2014</rights><rights>COPYRIGHT 2014 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 27, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c637t-f3f7129cb8ad68c52b36c1d5ef1a50c5ea59f9ac6326f7ee8e2bb01292d229d23</citedby><cites>FETCH-LOGICAL-c637t-f3f7129cb8ad68c52b36c1d5ef1a50c5ea59f9ac6326f7ee8e2bb01292d229d23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature12903$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature12903$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24413398$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Tae-Hee</creatorcontrib><creatorcontrib>Li, Fugen</creatorcontrib><creatorcontrib>Ferreiro-Neira, Isabel</creatorcontrib><creatorcontrib>Ho, Li-Lun</creatorcontrib><creatorcontrib>Luyten, Annouck</creatorcontrib><creatorcontrib>Nalapareddy, Kodandaramireddy</creatorcontrib><creatorcontrib>Long, Henry</creatorcontrib><creatorcontrib>Verzi, Michael</creatorcontrib><creatorcontrib>Shivdasani, Ramesh A.</creatorcontrib><title>Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>A study investigating the mechanisms underlying lateral inhibition and lineage plasticity in the mouse small intestine crypts
in vivo
finds that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and this is the basis of lateral inhibition.
Intestinal crypt differentiation
Intestinal crypts are the focus of intensive study, stimulated in part by the recent discovery of distinct stem-cell populations and markers. Ramesh Shivdasani and colleagues have studied mechanisms underlying lateral inhibition and lineage plasticity in mouse small intestine crypts
in vivo
. They find that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and that this is the basis of lateral inhibition.
Cells differentiate when transcription factors bind accessible
cis
-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem cells, chromatin at lineage-restricted genes becomes sequentially accessible
1
,
2
,
3
,
4
, probably by means of ‘pioneer’ transcription factor activity
5
, but tissues may use other strategies
in vivo
. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbours
6
, and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where notch signalling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages
7
,
8
,
9
. Transcript profiles in isolated LGR5
+
intestinal stem cells
10
and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNase I hypersensitivity—signifying accessible, permissive chromatin—at most of the same
cis
-elements. Enhancers acting uniquely in progenitors were well demarcated in LGR5
+
intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific transcription factor, controls lateral inhibition through delta-like notch ligand genes and also drives the expression of numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to the presence or absence of a key transcription factor. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted transcription factor with broadly permissive chromatin established in multipotent stem cells.</description><subject>13/100</subject><subject>13/51</subject><subject>38</subject><subject>45</subject><subject>45/15</subject><subject>631/136/142</subject><subject>631/532/2437</subject><subject>64</subject><subject>64/60</subject><subject>Animals</subject><subject>Basic Helix-Loop-Helix Transcription Factors - deficiency</subject><subject>Basic Helix-Loop-Helix Transcription Factors - metabolism</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Lineage - genetics</subject><subject>Cell research</subject><subject>Chromatin</subject><subject>Chromatin - genetics</subject><subject>Chromatin - metabolism</subject><subject>Deoxyribonuclease I - metabolism</subject><subject>DNA methylation</subject><subject>Enhancer Elements, Genetic - genetics</subject><subject>Enterocytes - cytology</subject><subject>Enterocytes - metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Genetic transcription</subject><subject>Genomics</subject><subject>Histones - metabolism</subject><subject>Humanities and Social Sciences</subject><subject>Hypersensitivity</subject><subject>Inhibition</subject><subject>Intestine, Small - cytology</subject><subject>Intestine, Small - metabolism</subject><subject>letter</subject><subject>Ligands</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>multidisciplinary</subject><subject>Physiological aspects</subject><subject>Plasticity</subject><subject>Receptors, Notch - metabolism</subject><subject>Rodents</subject><subject>Science</subject><subject>Stem cells</subject><subject>Stem Cells - cytology</subject><subject>Stem Cells - metabolism</subject><subject>Transcription 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permissive intestinal chromatin underlies lateral inhibition and cell plasticity</title><author>Kim, Tae-Hee ; Li, Fugen ; Ferreiro-Neira, Isabel ; Ho, Li-Lun ; Luyten, Annouck ; Nalapareddy, Kodandaramireddy ; Long, Henry ; Verzi, Michael ; Shivdasani, Ramesh A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c637t-f3f7129cb8ad68c52b36c1d5ef1a50c5ea59f9ac6326f7ee8e2bb01292d229d23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>13/100</topic><topic>13/51</topic><topic>38</topic><topic>45</topic><topic>45/15</topic><topic>631/136/142</topic><topic>631/532/2437</topic><topic>64</topic><topic>64/60</topic><topic>Animals</topic><topic>Basic Helix-Loop-Helix Transcription Factors - deficiency</topic><topic>Basic Helix-Loop-Helix Transcription Factors - metabolism</topic><topic>Cell differentiation</topic><topic>Cell Differentiation - genetics</topic><topic>Cell Lineage - genetics</topic><topic>Cell research</topic><topic>Chromatin</topic><topic>Chromatin - genetics</topic><topic>Chromatin - metabolism</topic><topic>Deoxyribonuclease I - metabolism</topic><topic>DNA methylation</topic><topic>Enhancer Elements, Genetic - genetics</topic><topic>Enterocytes - cytology</topic><topic>Enterocytes - metabolism</topic><topic>Female</topic><topic>Gene Expression Regulation</topic><topic>Genetic transcription</topic><topic>Genomics</topic><topic>Histones - metabolism</topic><topic>Humanities and Social Sciences</topic><topic>Hypersensitivity</topic><topic>Inhibition</topic><topic>Intestine, Small - cytology</topic><topic>Intestine, Small - metabolism</topic><topic>letter</topic><topic>Ligands</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>multidisciplinary</topic><topic>Physiological aspects</topic><topic>Plasticity</topic><topic>Receptors, Notch - metabolism</topic><topic>Rodents</topic><topic>Science</topic><topic>Stem 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(London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2014-02-27</date><risdate>2014</risdate><volume>506</volume><issue>7489</issue><spage>511</spage><epage>515</epage><pages>511-515</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>A study investigating the mechanisms underlying lateral inhibition and lineage plasticity in the mouse small intestine crypts
in vivo
finds that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and this is the basis of lateral inhibition.
Intestinal crypt differentiation
Intestinal crypts are the focus of intensive study, stimulated in part by the recent discovery of distinct stem-cell populations and markers. Ramesh Shivdasani and colleagues have studied mechanisms underlying lateral inhibition and lineage plasticity in mouse small intestine crypts
in vivo
. They find that crypt cells maintain a permissive chromatin state upon which a transcription factor acts to determine lineage specification, and that this is the basis of lateral inhibition.
Cells differentiate when transcription factors bind accessible
cis
-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem cells, chromatin at lineage-restricted genes becomes sequentially accessible
1
,
2
,
3
,
4
, probably by means of ‘pioneer’ transcription factor activity
5
, but tissues may use other strategies
in vivo
. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbours
6
, and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where notch signalling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages
7
,
8
,
9
. Transcript profiles in isolated LGR5
+
intestinal stem cells
10
and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNase I hypersensitivity—signifying accessible, permissive chromatin—at most of the same
cis
-elements. Enhancers acting uniquely in progenitors were well demarcated in LGR5
+
intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific transcription factor, controls lateral inhibition through delta-like notch ligand genes and also drives the expression of numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to the presence or absence of a key transcription factor. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted transcription factor with broadly permissive chromatin established in multipotent stem cells.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24413398</pmid><doi>10.1038/nature12903</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2014-02, Vol.506 (7489), p.511-515 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4151315 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 13/100 13/51 38 45 45/15 631/136/142 631/532/2437 64 64/60 Animals Basic Helix-Loop-Helix Transcription Factors - deficiency Basic Helix-Loop-Helix Transcription Factors - metabolism Cell differentiation Cell Differentiation - genetics Cell Lineage - genetics Cell research Chromatin Chromatin - genetics Chromatin - metabolism Deoxyribonuclease I - metabolism DNA methylation Enhancer Elements, Genetic - genetics Enterocytes - cytology Enterocytes - metabolism Female Gene Expression Regulation Genetic transcription Genomics Histones - metabolism Humanities and Social Sciences Hypersensitivity Inhibition Intestine, Small - cytology Intestine, Small - metabolism letter Ligands Male Mice Mice, Inbred C57BL multidisciplinary Physiological aspects Plasticity Receptors, Notch - metabolism Rodents Science Stem cells Stem Cells - cytology Stem Cells - metabolism Transcription factors Transcription, Genetic |
| title | Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-15T19%3A58%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Broadly%20permissive%20intestinal%20chromatin%20underlies%20lateral%20inhibition%20and%20cell%20plasticity&rft.jtitle=Nature%20(London)&rft.au=Kim,%20Tae-Hee&rft.date=2014-02-27&rft.volume=506&rft.issue=7489&rft.spage=511&rft.epage=515&rft.pages=511-515&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature12903&rft_dat=%3Cgale_pubme%3EA362849929%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1508489705&rft_id=info:pmid/24413398&rft_galeid=A362849929&rfr_iscdi=true |