SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling

Gu, Wei Yong; Wang, Hua; Huang, Xiaofeng; Kraiczy, Judith; Singh, Pratik; Ng, Charles Wang Wai; Dagdeviren, Sezin; Houghton, Sean; Pellón-Cárdenas, Oscar; Lan, Ying; Nie, Yaohui; Zhang, Jiaoyue; Banerjee, Kushal K.; Onufer, Emily J.; Warner, Brad W.; Spence, Jason R.; Scherl, Ellen; Rafii, Shahin; Lee, Richard T.; Verzi, Michael P.; Redmond, David; Longman, Randy S.; Helin, Kristian; Shivdasani, Ramesh A.; Zhou, Qiao

doi:10.1016/j.stem.2021.09.004

Cited by 39 publications

(32 citation statements)

References 88 publications

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“…Each symbol presents one dataset: gray square ■ = GSE156453, 39 white square □ = Ma'ayeh et al. ; 44 black circle ● = GSE164334, 38 black triangle ▲ = GSE160695, 43 white circle ○ = GSE163706, 42 black square ◆ = GSE127938, 40 gray circle = GSE167286, 41 black star ★ = own data 15 (values are shown as mean ± SEM)…”

Section: Resultsmentioning

confidence: 99%

“…Comparison of the qualitative expression of typical transporter genes between Caco‐2, tissue, ODMs, and organoids was performed using the following data sets, available at Gene Expression Omnibus (GEO): GSE164334, 38 GSE156453, 39 GSE127938, 40 GSE167286, 41 GSE163706, and 42 GSE160695; 43 and one data set from Ma'ayeh et al. 44 and our own data 15 .…”

Section: Methodsmentioning

confidence: 99%

“…Comparison of the qualitative expression of typical transporter genes between Caco-2, tissue, ODMs, and organoids was performed using the following data sets, available at Gene Expression Omnibus (GEO): GSE164334, 38 GSE156453, 39 GSE127938, 40 GSE167286, 41 GSE163706, and 42 GSE160695; 43 and one data set from Ma'ayeh et al 44 and our own data. 15 Since these data were obtained using different methods (RNAseq and DNA microarray), they were only qualitatively evaluated according to whether transporters were reported to be expressed.…”

Section: Transcriptomic Analysismentioning

confidence: 99%

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Human duodenal organoid‐derived monolayers serve as a suitable barrier model for duodenal tissue

Weiß

Holthaus

Kraft

et al. 2022

Annals of the New York Academy of Sciences

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Usually, duodenal barriers are investigated using intestinal cell lines like Caco-2, which in contrast to native tissue are limited in cell-type representation. Organoids can consist of all intestinal cell types and are supposed to better reflect the in vivo situation.Growing three-dimensionally, with the apical side facing the lumen, application of typical physiological techniques to analyze the barrier is difficult. Organoid-derived monolayers (ODMs) were developed to overcome this. After optimizing culturing conditions, ODMs were characterized and compared to Caco-2 and duodenal tissue. Tight junction composition and appearance were analyzed, and electrophysiological barrier properties, like paracellular and transcellular barrier function and macromolecule permeability, were evaluated. Furthermore, transcriptomic data were analyzed. ODMs had tight junction protein expression and paracellular barrier properties much more resembling the originating tissue than Caco-2. Transcellular barrier was similar between ODMs and native tissue but was increased in Caco-2. Transcriptomic data showed that Caco-2 expressed fewer solute carriers than ODMs and native tissue. In conclusion, while Caco-2 cells differ mostly in transcellular properties, ODMs reflect trans-and paracellular properties of the originating tissue. If cultured under optimized conditions, ODMs possess reproducible functionality, and the variety of different cell types makes them a suitable model for human tissue-specific investigations.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Transcriptomic Analysismentioning

confidence: 99%

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Human duodenal organoid‐derived monolayers serve as a suitable barrier model for duodenal tissue

Weiß

Holthaus

Kraft

et al. 2022

Annals of the New York Academy of Sciences

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“…It has been shown that SATB2 is constitutively expressed in colonic mucosa. A recent murine study showed that colonic stem cell identity was lost when SATB2 expression was lost; inversely, the gain of SATB2 expression in small bowel stem cells leads to the conversion into the colonic phenotype 6 . In human pathology, SATB2-immunohistochemistry has gained importance over the last two decades as a marker of osteosarcoma 7 , 8 .…”

Section: Introductionmentioning

confidence: 99%

Loss of SATB2 expression correlates with cytokeratin 7 and PD-L1 tumor cell positivity and aggressiveness in colorectal cancer

Hrudka

Matěj

Nikov

et al. 2022

Sci Rep

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Colorectal carcinoma (CRC) is a disease that causes significant morbidity and mortality worldwide. To improve treatment, new biomarkers are needed to allow better patient risk stratification in terms of prognosis. This study aimed to clarify the prognostic significance of colonic-specific transcription factor special AT-rich sequence-binding protein 2 (SATB2), cytoskeletal protein cytokeratin 7 (CK7), and immune checkpoint molecule programmed death-ligand 1 (PD-L1). We analyzed a cohort of 285 patients with surgically treated CRC for quantitative associations among the three markers and five traditional prognostic indicators (i.e., tumor stage, histological grade, variant morphology, laterality, and mismatch-repair/MMR status). The results showed that loss of SATB2 expression had significant negative prognostic implications relative to overall survival (OS) and cancer-specific survival (CSS), significantly shortened 5 years OS and CSS and 10 years CSS in patients with CRC expressing CK7, and borderline insignificantly shortened OS in patients with PD-L1 + CRC. PD-L1 showed a significant negative impact in cases with strong expression (membranous staining in 50–100% of tumor cells). Loss of SATB2 was associated with CK7 expression, advanced tumor stage, mucinous or signet ring cell morphology, high grade, right-sided localization but was borderline insignificant relative to PD-L1 expression. CK7 expression was associated with high grade and SATB2 loss. Additionally, a separate analysis of 248 neoadjuvant therapy-naïve cases was performed with mostly similar results. The loss of SATB2 and CK7 expression were significant negative predictors in the multivariate analysis adjusted for associated parameters and patient age. In summary, loss of SATB2 expression and gain of CK7 and strong PD-L1 expression characterize an aggressive phenotype of CRC.

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“…We recently identified SATB2, a colon-restricted chromatin factor, as a central regulator of colonic gene expression and lineage plasticity 21 . Satb2 deletion converts colonic stem cells into small intestine ileum-like stem cells, leading to the replacement of colonic mucosa by ileum-like mucosa in adult mouse colon.…”

Section: Introductionmentioning

confidence: 99%

A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin

Huang

Singh

et al. 2022

Preprint

Self Cite

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Plasticity between cell lineages is a fundamental but poorly understood property of regenerative tissues. In the gut tube, small intestine absorbs nutrients whereas colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screen, we identified MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrain colonic plasticity. MTA2 loss in adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-binds with HNF4A, an activating pan-intestine transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic and gain on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through a HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages; their release unleashes plasticity.

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SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling

Cited by 39 publications

References 88 publications

Human duodenal organoid‐derived monolayers serve as a suitable barrier model for duodenal tissue

Human duodenal organoid‐derived monolayers serve as a suitable barrier model for duodenal tissue

Loss of SATB2 expression correlates with cytokeratin 7 and PD-L1 tumor cell positivity and aggressiveness in colorectal cancer

A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin

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