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1.
J Exp Med ; 220(10)2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37549024

RESUMO

The neuro-immune regulation is associated with homeostasis of the intestine. Intestinal group 3 innate lymphoid cells (ILC3s) are tissue-resident lymphocytes whose functions are affected by the intestine niche. However, how a gut neuronal signal coordinates the immune response of ILC3s is largely unknown. Here, we found that cyclic adenosine monophosphate (cAMP) signaling exacerbated the inflammatory response and attenuated the expression level of the transcription factor forkhead box O1 (FOXO1) in ILC3s. Deficiency of FOXO1 drove the hyperactivation of ILC3s and resulted in gut inflammation independently of T cells. Mechanistically, FOXO1 promoted the transcription of neuropeptide receptor VIPR2 and inhibited the transcription of adrenoceptor ADRA2A in ILC3s. FOXO1-related regulation of VIPR2 and ADRA2A signaling balanced the activation of ILC3s under steady condition or during colitis. Moreover, chronic stress elevated cAMP level and downregulated FOXO1 level, exacerbating intestinal inflammation. Our findings reveal that FOXO1 balances the activation of ILC3s via VIP and adrenergic signaling and regulates intestinal homeostasis.


Assuntos
Imunidade Inata , Linfócitos , Humanos , Transdução de Sinais , Inflamação/metabolismo , Homeostase , Proteína Forkhead Box O1/metabolismo
3.
EMBO J ; 42(6): e112039, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36715460

RESUMO

Intestinal stem cells (ISCs) at the crypt base are responsible for the regeneration of the intestinal epithelium. However, how ISC self-renewal is regulated still remains unclear. Here we identified a circular RNA, circBtnl1, that is highly expressed in ISCs. Loss of circBtnl1 in mice enhanced ISC self-renewal capacity and epithelial regeneration, without changes in mRNA and protein levels of its parental gene Btnl1. Mechanistically, circBtnl1 and Atf4 mRNA competitively bound the ATP-dependent RNA helicase Ddx3y to impair the stability of Atf4 mRNA in wild-type ISCs. Furthermore, ATF4 activated Sox9 transcription by binding to its promoter via a unique motif, to enhance the self-renewal capacity and epithelial regeneration of ISCs. In contrast, circBtnl1 knockout promoted Atf4 mRNA stability and enhanced ATF4 expression, which caused Sox9 transcription to potentiate ISC stemness. These data indicate that circBtnl1-mediated Atf4 mRNA decay suppresses Sox9 transcription that negatively modulates self-renewal maintenance of ISCs.


Assuntos
Fator 4 Ativador da Transcrição , Mucosa Intestinal , Estabilidade de RNA , RNA Circular , RNA Mensageiro , Regeneração , Células-Tronco , Células-Tronco/citologia , Células-Tronco/fisiologia , Organoides/citologia , Camundongos Endogâmicos C57BL , Animais , Camundongos , RNA Circular/genética , RNA Circular/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/fisiologia , Regeneração/genética , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , RNA Mensageiro/metabolismo , Ativação Transcricional , Fatores de Transcrição SOX9/genética , Antígenos de Histocompatibilidade Menor/metabolismo , RNA Helicases DEAD-box/metabolismo
4.
Fundam Res ; 3(5): 692-706, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38933287

RESUMO

Tumorigenesis is a complicated process in which numerous modulators are involved in different ways. Previous studies have focused primarily on tumor-associated protein-coding genes such as oncogenes and tumor suppressor genes, as well as their associated oncogenic pathways. However, noncoding RNAs (ncRNAs), rising stars in diverse physiological and pathological processes, have recently emerged as additional modulators in tumorigenesis. In this review, we focus on two typical kinds of ncRNAs: long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs). We describe the molecular patterns of ncRNAs and focus on the roles of ncRNAs in cancer stem cells (CSCs), tumor cells, and tumor environmental cells. CSCs are a small subset of tumor cells and are generally considered to be cells that initiate tumorigenesis, and dozens of ncRNAs have been defined as critical modulators in CSC maintenance and oncogenesis. Moreover, ncRNAs are widely involved in oncogenetic processes, including sustaining proliferation, resisting cell death, genome instability, metabolic disorders, immune escape and metastasis. We also discuss the potential applications of ncRNAs in tumor diagnosis and therapy. The progress in ncRNA research greatly improves our understanding of ncRNAs in oncogenesis and provides new potential targets for future tumor therapy.

6.
Nat Commun ; 13(1): 4711, 2022 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953472

RESUMO

Innate lymphoid cells (ILCs) exert important roles in host defense, tissue repair and inflammatory diseases. However, how ILC lineage specification is regulated remains largely elusive. Here we identify that circular RNA circTmem241 is highly expressed in group III innate lymphoid cells (ILC3s) and their progenitor cells. CircTmem241 deficiency impairs ILC3 commitment and attenuates anti-bacterial immunity. Mechanistically, circTmem241 interacts with Nono protein to recruit histone methyltransferase Ash1l onto Elk3 promoter in ILC progenitor cells (ILCPs). Ash1l-mediated histone modifications on Elk3 promoter enhance chromatin accessibility to initiate Elk3 transcription. Of note, circTmem241-/-, Nono-/- and Ash1l-/- ILCPs display impaired ILC3 differentiation, while Elk3 overexpression rescues ILC3 commitment ability. Finally, circTmem241-/-Elk3-/- mice show lower numbers of ILC3s and are more susceptible to bacterial infection. We reveal that the circTmem241-Nono-Ash1l-Elk3 axis is required for the ILCP differentiation into ILC3P and ILC3 maturation, which is important to manipulate this axis for ILC development on treatment of infectious diseases.


Assuntos
Imunidade Inata , Linfócitos , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Animais , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase , Linfócitos/metabolismo , Camundongos , RNA Circular , Fatores de Transcrição/metabolismo
7.
Neuron ; 110(14): 2268-2282.e4, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35550066

RESUMO

Colorectal cancer stem cells (CSCs) contribute to colorectal tumorigenesis and metastasis. Colorectal CSCs reside within specialized niches and harbor self-renewal and differentiation capacities. However, the niche regulations of CSCs remain unclear. Here, we show that intestinal nerve cells are required for CSC self-renewal and colorectal tumorigenesis. Enteric serotonergic neurons produce 5-hydroxytryptamine (5-HT) to function as a modulator of CSC self-renewal. 5-HT receptors HTR1B/1D/1F are highly expressed in colorectal CSCs and engage with 5-HT to initiate Wnt/ß-catenin signaling. Mechanistically, colorectal cancer (CRC)-enriched microbiota metabolite isovalerate suppresses the enrichment of the NuRD complex onto Tph2 promoter to initiate Tph2 expression, leading to 5-HT production. 5-HT signaling is correlated with CRC severity. Blocking 5-HT signaling in mice not only inhibits the self-renewal of colorectal CSCs but also displays therapeutic efficacy against CRC tumors. Our findings reveal a cross talk between intestinal neurons and tumor cells that serves as an additional layer for CSC regulation.


Assuntos
Autorrenovação Celular , Neoplasias Colorretais , Animais , Carcinogênese , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Camundongos , Neurônios Serotoninérgicos/metabolismo , Serotonina , Via de Sinalização Wnt
8.
Cell Res ; 32(6): 555-569, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35379903

RESUMO

Lgr5+ intestinal stem cells (ISCs) reside within specialized niches at the crypt base and harbor self-renewal and differentiation capacities. ISCs in the crypt base are sustained by their surrounding niche for precise modulation of self-renewal and differentiation. However, how intestinal cells in the crypt niche and microbiota in enteric cavity coordinately regulate ISC stemness remains unclear. Here, we show that ISCs are regulated by microbiota and niche enteric serotonergic neurons. The gut microbiota metabolite valeric acid promotes Tph2 expression in enteric serotonergic neurons via blocking the recruitment of the NuRD complex onto Tph2 promoter. 5-hydroxytryptamine (5-HT) in turn activates PGE2 production in a PGE2+ macrophage subset through its receptors HTR2A/3 A; and PGE2 via binding its receptors EP1/EP4, promotes Wnt/ß-catenin signaling in ISCs to promote their self-renewal. Our findings illustrate a complex crosstalk among microbiota, intestinal nerve cells, intestinal immune cells and ISCs, revealing a new layer of ISC regulation by niche cells and microbiota.


Assuntos
Microbioma Gastrointestinal , Autorrenovação Celular , Dinoprostona/metabolismo , Mucosa Intestinal/metabolismo , Intestinos , Macrófagos , Neurônios Serotoninérgicos , Células-Tronco
9.
Immunity ; 55(4): 686-700.e7, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35320705

RESUMO

Tuft cells are a type of intestinal epithelial cells that exist in epithelial barriers and play a critical role in immunity against parasite infection. It remains insufficiently clear whether Tuft cells participate in bacterial eradication. Here, we identified Sh2d6 as a signature marker for CD45+ Tuft-2 cells. Depletion of Tuft-2 cells resulted in susceptibility to bacterial infection. Tuft-2 cells quickly expanded in response to bacterial infection and sensed the bacterial metabolite N-undecanoylglycine through vomeronasal receptor Vmn2r26. Mechanistically, Vmn2r26 engaged with N-undecanoylglycine activated G-protein-coupled receptor-phospholipase C gamma2 (GPCR-PLCγ2)-Ca2+ signaling axis, which initiated prostaglandin D2 (PGD2) production. PGD2 enhanced the mucus secretion of goblet cells and induced antibacterial immunity. Moreover, Vmn2r26 signaling also promoted SpiB transcription factor expression, which is responsible for Tuft-2 cell development and expansion in response to bacterial challenge. Our findings reveal an additional function of Tuft-2 cells in immunity against bacterial infection through Vmn2r26-mediated recognition of bacterial metabolites.


Assuntos
Anti-Infecciosos , Mucosa Intestinal , Antibacterianos , Anti-Infecciosos/metabolismo , Células Caliciformes , Prostaglandina D2/metabolismo
10.
Cell Mol Immunol ; 19(5): 619-633, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35301470

RESUMO

Neutrophils are derived from bone marrow hematopoietic stem cells (HSCs) and are the largest population among circulating white blood cells in humans, acting as the first line of defense against invading pathogens. Whether neutrophils can be generated by transdifferentiation strategies is unknown. Here, we show that thymidine induces the conversion of mouse fibroblasts to neutrophils. Induced neutrophils (iNeus) showed antibacterial effects and did not undergo malignant transformation in vivo. Importantly, iNeu transplantation cured neutropenia in mice in vivo. Mechanistically, thymidine mediates iNeu conversion by enhancing Tet3 activity. Tet3 initiates the expression of the neutrophil fate decision factors Cebpδ and Rfx1 that drive the transdifferentiation of mouse fibroblasts to neutrophils. Therefore, the induction of functional neutrophils by chemicals may provide a potential therapeutic strategy for patients with neutropenia patients and infectious diseases.Fibroblasts; Neutrophils; Thymidine; Transdifferentiation; Tet3.


Assuntos
Dioxigenases , Neutropenia , Animais , Dioxigenases/metabolismo , Fibroblastos/metabolismo , Humanos , Camundongos , Neutropenia/metabolismo , Neutropenia/patologia , Neutrófilos/metabolismo , Fator Regulador X1/metabolismo , Timidina/metabolismo
11.
Nat Commun ; 12(1): 6314, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728628

RESUMO

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N1-methyladenosine methylation (m1A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m1A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer.


Assuntos
Adenosina/análogos & derivados , Carcinoma Hepatocelular/patologia , Colesterol/metabolismo , Proteínas de Membrana/metabolismo , PPAR gama/metabolismo , RNA de Transferência/metabolismo , tRNA Metiltransferases/metabolismo , Adenosina/química , Adenosina/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Autorrenovação Celular , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Proteínas de Membrana/genética , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Taxa de Sobrevida , tRNA Metiltransferases/genética
12.
Mol Cancer ; 20(1): 132, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649567

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity. Liver cancer initiating cells also called cancer stem cells (CSCs) play a critical role in resistance against typical therapy and high tumor-initiating potential. However, the role of the novel circular RNA (circRNA) circIPO11 in the maintenance of liver cancer initiating cells remains elusive. METHODS: CircRNAs highly conserved in humans and mice were identified from 3 primary HCC samples by circRNA array. The expression and function of circIPO11 were further evaluated by Northern blot, limiting dilution xenograft analysis, chromatin isolation by RNA purification-PCR assay (ChIRP) and HCC patient-derived tumor cells (PDC) models. CircIpo11 knockout (KO) mice were generated by a CRISPR/Cas9 technology. RESULTS: CircIPO11 is highly expressed in HCC tumor tissues and liver CSCs. CircIPO11 is required for the self-renewal maintenance of liver CSCs to initiate HCC development. Mechanistically, circIPO11 recruits TOP1 to GLI1 promoter to trigger its transcription, leading to the activation of Hedgehog signaling. Moreover, GLI1 is also highly expressed in HCC tumor tissues and liver CSCs, and TOP1 expression levels positively correlate with the metastasis, recurrence and survival of HCC patients. Additionally, circIPO11 knockout in mice suppresses the progression of chemically induced liver cancer development. CONCLUSION: Our findings reveal that circIPO11 drives the self-renewal of liver CSCs and promotes the propagation of HCC via activating Hedgehog signaling pathway. Antisense oligonucleotides (ASOs) against circIPO11 combined with TOP1 inhibitor camptothecin (CPT) exert synergistic antitumor effect. Therefore, circIPO11 and the Hedgehog signaling pathway may provide new potential targets for the treatment of HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Autorrenovação Celular/genética , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Circular , beta Carioferinas/genética , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Suscetibilidade a Doenças , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/patologia , Regiões Promotoras Genéticas , Transdução de Sinais
13.
J Clin Invest ; 131(19)2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34403373

RESUMO

Liver tumor-initiating cells (TICs) are involved in liver tumorigenesis, metastasis, drug resistance, and relapse, but the regulatory mechanisms of liver TICs are largely unknown. Here, we have identified a functional circular RNA, termed circRNA activating MAFF (cia-MAF), that is robustly expressed in liver cancer and liver TICs. cia-MAF-KO primary cells and cia-maf-KO liver tumors harbor decreased ratios of TICs, and display impaired liver tumorigenesis, self-renewal, and metastatic capacities. In contrast, cia-MAF overexpression drives liver TIC propagation, self-renewal, and metastasis. Mechanistically, cia-MAF binds to the MAFF promoter, recruits the TIP60 complex to the MAFF promoter, and finally promotes MAFF expression. Loss of cia-MAF function attenuates the combination between the TIP60 complex and the MAFF promoter. MAFF is highly expressed in liver tumors and liver TICs, and its antisense oligo (ASO) has therapeutic potential in treating liver cancer without MAFA/MAFG gene copy number alterations (CNAs). This study reveals an additional layer for liver TIC regulation as well as circRNA function, and provides an additional target for eliminating liver TICs, especially for liver tumors without MAFA/MAFG gene CNAs.


Assuntos
Autorrenovação Celular , Neoplasias Hepáticas/etiologia , Fator de Transcrição MafF/fisiologia , Células-Tronco Neoplásicas/fisiologia , RNA Circular/fisiologia , Animais , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Lisina Acetiltransferase 5/genética , Lisina Acetiltransferase 5/fisiologia , Fator de Transcrição MafF/genética , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Regiões Promotoras Genéticas
14.
Cell Rep ; 36(4): 109431, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34320348

RESUMO

Colorectal cancer (CRC) is one of the most common cancers worldwide, in which adenomatous polyposis coli (APC) mutations are frequently and uniquely observed. Here we find that cis-HOX (circular RNA stabilizing HOXC10) is robustly expressed in colorectal tumor-initiating cells (TICs). cis-HOX knockout decreases colorectal TIC numbers and impairs the self-renewal, tumorigenesis, and metastatic capacities of TICs, whereas cis-HOX overexpression drives colorectal TIC self-renewal and metastasis. Mechanistically, cis-HOX binds to HOXC10 mRNA to attenuate its decay through blocking the K-homology splicing regulatory protein (KSRP)-binding sequence of HOXC10 3' UTR. HOXC10 is highly expressed in colorectal tumors and TICs and triggers Wnt/ß-catenin activation by activating FZD3 expression. HOXC10 inhibitor salinomycin exerts efficient therapeutic effects in APC-wild-type colorectal tumors, but not in tumors with APC nonsense mutations. Therefore, the cis-HOX-HOXC10 pathway drives colorectal tumorigenesis, stemness, and metastasis and serves as a potential therapeutic target for APC-wild-type colorectal tumors.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas de Homeodomínio/metabolismo , Terapia de Alvo Molecular , Mutação/ética , Células-Tronco Neoplásicas/patologia , RNA Circular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular , Feminino , Receptores Frizzled/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos Knockout , Células-Tronco Neoplásicas/metabolismo , Piranos/farmacologia , Estabilidade de RNA/genética , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Via de Sinalização Wnt
15.
Cell Mol Immunol ; 18(6): 1412-1424, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33911218

RESUMO

Group 3 innate lymphoid cells (ILC3s) play critical roles in innate immunity and gut homeostasis. However, how ILC3 homeostasis is regulated remains elusive. Here, we identified a novel circular RNA, circZbtb20, that is highly expressed in ILC3s and required for their maintenance and function. CircZbtb20 deletion causes reduced ILC3 numbers, increasing susceptibility to C. rodentium infection. Mechanistically, circZbtb20 enhances the interaction of Alkbh5 with Nr4a1 mRNA, leading to ablation of the m6A modification of Nr4a1 mRNA to promote its stability. Nr4a1 initiates Notch2 signaling activation, which contributes to the maintenance of ILC3 homeostasis. Deletion of Alkbh5 or Nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection. Thus, our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.


Assuntos
Adenosina/análogos & derivados , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Desmetilação , Homeostase , Imunidade Inata/genética , Linfócitos/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , RNA Circular/metabolismo , Adenosina/metabolismo , Animais , Proliferação de Células , Sobrevivência Celular , Trato Gastrointestinal/imunologia , Camundongos Knockout , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Ligação Proteica , Estabilidade de RNA , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Notch2/metabolismo , Transdução de Sinais
16.
Nat Commun ; 11(1): 4076, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796851

RESUMO

Group 3 innate lymphoid cells (ILC3) are an important regulator for immunity, inflammation and tissue homeostasis in the intestine, but how ILC3 activation is regulated remains elusive. Here we identify a new circular RNA (circRNA) circKcnt2 that is induced in ILC3s during intestinal inflammation. Deletion of circKcnt2 causes gut ILC3 activation and severe colitis in mice. Mechanistically, circKcnt2, as a nuclear circRNA, recruits the nucleosome remodeling deacetylase (NuRD) complex onto Batf promoter to inhibit Batf expression; this in turn suppresses Il17 expression and thereby ILC3 inactivation to promote innate colitis resolution. Furthermore, Mbd3-/-Rag1-/- and circKcnt2-/-Rag1-/- mice develop severe innate colitis following dextran sodium sulfate (DSS) treatments, while simultaneous deletion of Batf promotes colitis resolution. In summary, our data support a function of the circRNA circKcnt2 in regulating ILC3 inactivation and resolution of innate colitis.


Assuntos
Colite/imunologia , Colite/metabolismo , Linfócitos/metabolismo , Canais de Potássio Ativados por Sódio/metabolismo , RNA Circular/metabolismo , Animais , Colite/patologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Proteínas de Homeodomínio/genética , Homeostase , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/patologia , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Canais de Potássio Ativados por Sódio/genética , RNA Circular/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Fatores de Transcrição/genética
17.
Cell Res ; 30(7): 630, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32541864

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

18.
Cell Res ; 30(7): 610-622, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32367039

RESUMO

Innate lymphoid cells (ILCs) reside in mucosal surfaces to potentiate immune responses, sustain mucosal integrity and maintain tissue homeostasis. However, how tumor infiltrating ILCs modulate tumor development and progression is unclear. Here we profiled tumor infiltrating ILCs during colorectal cancer (CRC) progression by single-cell RNA sequencing. We identified six clusters of tumor infiltrating ILCs with unique features. ILC1s expressed inhibitory receptors and underwent inhibitory functional conversion at the late stage of CRC. ILC2s were classified into three subsets (called ILC2-A, -B, -C), of which ILC2-C subset could facilitate tumor progression. HS3ST1 and PD1 were highly expressed in ILC2s of late stage CRC tumors and deficiency of HS3ST1 or PD1 in ILC2s suppressed tumor growth. Moreover, ILC3s transdifferentiated into ILCregs during CRC progression and ILCregs promoted tumor growth. Of note, TGF-ß signaling initiated the conversion of ILC3s to ILCregs and blockade of TGF-ß signaling could disrupt the ILCreg transdifferentiation and inhibited tumor growth. Thus, intervention of ILC conversions might be a potential strategy for CRC immunotherapy.


Assuntos
Transdiferenciação Celular , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Progressão da Doença , Imunidade Inata , Linfócitos do Interstício Tumoral/patologia , Linfócitos/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Fator de Crescimento Transformador beta/metabolismo
19.
EMBO J ; 39(13): e103786, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32449550

RESUMO

Lgr5+ intestinal stem cells (ISCs) exhibit self-renewal and differentiation features under homeostatic conditions, but the mechanisms controlling Lgr5 + ISC self-renewal remain elusive. Here, we show that the chromatin remodeler SRCAP is highly expressed in mouse intestinal epithelium and ISCs. Srcap deletion impairs both self-renewal of ISCs and intestinal epithelial regeneration. Mechanistically, SRCAP recruits the transcriptional regulator REST to the Prdm16 promoter and induces expression of this transcription factor. By activating PPARδ expression, Prdm16 in turn initiates PPARδ signaling, which sustains ISC stemness. Rest or Prdm16 deficiency abrogates the self-renewal capacity of ISCs as well as intestinal epithelial regeneration. Collectively, these data show that the SRCAP-REST-Prdm16-PPARδ axis is required for self-renewal maintenance of Lgr5 + ISCs.


Assuntos
Adenosina Trifosfatases/metabolismo , Mucosa Intestinal/enzimologia , Transdução de Sinais , Células-Tronco/enzimologia , Adenosina Trifosfatases/genética , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Mucosa Intestinal/citologia , Camundongos , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Células-Tronco/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
20.
J Exp Med ; 217(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31699823

RESUMO

All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here, we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhances Hoxa1 expression, leading to HSC self-renewal. Bap1E651A mice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.


Assuntos
Autorrenovação Celular/genética , Ácido Glutâmico/metabolismo , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação/genética , Animais , Transplante de Medula Óssea , Sistemas CRISPR-Cas , Proteínas de Transporte/metabolismo , Células Cultivadas , Feminino , Granzimas/metabolismo , Células HEK293 , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Camundongos Knockout , Peptídeo Sintases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética
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