Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity

Kim, Tae-Hee; Li, Fugen; Ferreiro-Neira, Isabel; Ho, Li‐Lun; Luyten, Annouck; Nalapareddy, Kodandaramireddy; Long, Henry W.; Verzi, Michael P.; Shivdasani, Ramesh A.

doi:10.1038/nature12903

Cited by 226 publications

(249 citation statements)

References 41 publications

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“…This context-independent binding to cognate E-boxes has also been shown for the Drosophila Atonal protein (24). Despite this, the Atoh1 binding sites found in intestinal secretory cells show only a small overlap with those found in cerebellum granule neurons (951 out of 8729 detected in the gut) (23). So far, there are no data on Atoh1 binding sites in hair cells or dorsal interneurons: Atoh1 ChIP-seq experiments are problematic due to the very small numbers of these cell types (25,26 (27).…”

Section: Context Dependence Of Atoh1supporting

confidence: 52%

“…The idea that Atoh1 regulates distinct targets in different cell types has been borne out in recent studies that have employed ChIP-seq to determine Atoh1 binding sites in cerebellum granule neurons (22) and intestinal secretory cells (23). Both studies identified a similar Atoh1 DNA binding motif (brain: (G/A)(C/A)CA(G/T)(C/A)TG(G/T)(C/T) and intestine: CA(G/C)CTG(G/T)(C/T)) indicating that differences in cellular context do not appear to strongly affect Atoh1 preference for its unique E-box motif (Fig.…”

Section: Context Dependence Of Atoh1mentioning

confidence: 99%

“…To identify active and poised enhancers as well as tissue-specific chromatin access, techniques for genome-wide chromatin profiling, such as DNase1 hypersensitivity, have been applied to intestinal crypt progenitors in the presence or absence of Atoh1 (23). Enhancers normally bound by Atoh1 showed the same chromatin access and histone activation pattern in Atoh1 depleted crypt progenitors (23), indicating that Atoh1 does not control the initiation and maintenance of chromatin accessibility and epigenetic modification changes in intestinal progenitors. It therefore seems likely that chromatin remodeling precedes Atoh1 binding, raising the possibility that the chromatin landscape may have a prominent role in controlling Atoh1 activity.…”

Section: Chromatin Landscape and Epigenetic Modificationsmentioning

confidence: 99%

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Atoh1 in sensory hair cell development: constraints and cofactors

Costa

Powell

Lowell

et al. 2017

Seminars in Cell & Developmental Biology

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The proneural gene, Atoh1, is necessary and in some contexts sufficient for early inner ear hair cell development. Its function is the subject of intensive research, not least because of the possibility that it could be used in therapeutic strategies to reverse hair cell loss in deafness. However, it is clear that Atoh1's function is highly context dependent. During inner ear development, Atoh1 is only able to promote hair cell differentiation at specific developmental stages. Outside the ear, Atoh1 is required for differentiation of a variety of other cell types, for example in the intestine and cerebellum. The reasons for this context dependence are poorly understood. So far, the pathways and key players that instruct Atoh1 to act as a mechanosensory cell fate determinant in the context of the inner ear are largely unknown. Here we review evidence that suggests that Atoh1 function in hair cell differentiation is modulated by interaction with other transcription factors. We particularly focus on the possible roles of Gfi1 and Pou4f3, drawing from studies in mouse, Drosophila and C. elegans.3

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Section: Context Dependence Of Atoh1supporting

confidence: 52%

Section: Context Dependence Of Atoh1mentioning

confidence: 99%

Section: Chromatin Landscape and Epigenetic Modificationsmentioning

confidence: 99%

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Atoh1 in sensory hair cell development: constraints and cofactors

Costa

Powell

Lowell

et al. 2017

Seminars in Cell & Developmental Biology

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“…To determine whether altered Tgfβ signaling had gene expression enrichment for secretory precursor cell genes, we again started by using GSEA (32) and comparing secretory progenitors with enterocytes (34). GSEA on the microarray data showed that the Tgfβ inhibitor resulted in decreased expression of genes characteristic of secretory precursor cells, whereas Tgfβ ligand treatment showed increased expression of the same genes (Fig.…”

Section: Cultured Intestinal Enteroids Reveal a Role For Tgfβ Signalimentioning

confidence: 99%

Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

Fischer

Calabrese

Miller

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Intestinal stem cells (ISCs) are maintained by a niche mechanism, in which multiple ISCs undergo differential fates where a single ISC clone ultimately occupies the niche. Importantly, mutations continually accumulate within ISCs creating a potential competitive niche environment. Here we use single cell lineage tracing following stochastic transforming growth factor β receptor 2 (TgfβR2) mutation to show cell autonomous effects of TgfβR2 loss on ISC clonal dynamics and differentiation. Specifically, TgfβR2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgfβ signaling controls both ISC clone extinction and expansion, independent of proliferation. In addition, TgfβR2 loss in vivo reduced crypt fission, irradiation-induced crypt regeneration, and differentiation toward Paneth cells. Finally, altered Tgfβ signaling in cultured mouse and human enteroids supports further the in vivo data and reveals a critical role for Tgfβ signaling in generating precursor secretory cells. Overall, our data reveal a key role for Tgfβ signaling in regulating ISCs clonal dynamics and differentiation, with implications for cancer, tissue regeneration, and inflammation.T he intestinal epithelium is constantly renewed by proliferating, multipotent, and self-renewing intestinal stem cells (ISCs) (1). There are two main populations of ISCs: (i) a proliferating ISC population that is important for homeostasis of the niche residing below the +4 position and expressing a set of markers [e.g., leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) and Olfm4] and (ii) a quiescent ISC population residing near the +4 position and expressing a different set of markers (e.g., Bmi1 and Hopx) (2). Proliferating ISCs are the workhorses during normal homeostasis and are maintained within the niche by a close relationship with Paneth cells (3) and the stroma (4). The proliferating ISC population can be further divided into a smaller number (4-8) of functional ISCs (5,6

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“…The power of the microenvironment on cell plasticity, apart from cellintrinsic mechanisms, has been detected as well during normal homeostatic lineage differentiation of untransformed intestinal stem cells (ISM), demonstrating that epithelial lineage separation is reversible and therefore not a true lineage commitment. Kim et al [63] showed that ISC are equipotent, and lineage differentiation from ISC does not require differential chromatin priming, as progenitors for different lineages display comparable histone modifications and chromatin access regions, and are rather dependent on environmental stimuli and rely on transcription factor activity (Atoh1) for determining the fate of stem cells or the reversion of differentiated cells into ISM.…”

Section: Inflammatory Microenvironment: Inflammatory Mediators Inducementioning

confidence: 99%

Tumor cell plasticity: the challenge to catch a moving target

Schwitalla

2014

J Gastroenterol

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Every cancer cell is ''different''-within one and the same tumor, between different lesions originating from the same tumor, among different patients suffering from the same tumor type, and certainly between different tumor types. The complexity of tumor development, with its genetic, phenotypic and functional heterogeneity and plasticity within tumors and between primary tumors and metastases, underlies the unpredictable influences and stimuli of a tumor-associated inflammatory microenvironment, immune response, mechanical and metabolic stress, therapy-induced inflammation or interaction with microbiota. The stochastic and context dependent nature of these factors accounts for the difficulties to investigate the impact of resulting cell plasticity on tumor development, and justifies the challenge to prevent tumor recurrence. The emerging concept of cell plasticity and reciprocity (to change the phenotype by processing signals from the environment) throws more light on the actual complexity of tumor heterogeneity than can be expected solely from a unidirectional, classical cancer stem cell (CSC) model. To date, it remains widely unclear to what extent cell plasticity impacts tumor development, and it is difficult to assess by current methods. As a high tumor plasticity is likely to predict a poor outcome for patients, the future therapeutic challenge will be the development of personalized treatment strategies to predict and finally prevent cell plasticity in patients.

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Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity

Cited by 226 publications

References 41 publications

Atoh1 in sensory hair cell development: constraints and cofactors

Atoh1 in sensory hair cell development: constraints and cofactors

Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

Tumor cell plasticity: the challenge to catch a moving target

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