Journal ArticleDOI
The Lin28b–let-7–Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells
Michael R. Copley,Sonja Babovic,Claudia Benz,David J.H.F. Knapp,Philip A. Beer,David G. Kent,Stefan Wöhrer,David Q. Treloar,Christopher Day,Keegan Rowe,Heidi Mader,Florian Kuchenbauer,R. Keith Humphries,R. Keith Humphries,Connie J. Eaves,Connie J. Eaves +15 more
Reads0
Chats0
TLDR
Mouse haematopoietic stem cells undergo a postnatal transition in several properties, including a marked reduction in their self-renewal activity, and it is shown that the developmentally timed change in this key function of HSCs is associated with their decreased expression of Lin28b and an accompanying increase in their let-7 microRNA levels.Abstract:
Mouse haematopoietic stem cells (HSCs) undergo a postnatal transition in several properties, including a marked reduction in their self-renewal activity. We now show that the developmentally timed change in this key function of HSCs is associated with their decreased expression of Lin28b and an accompanying increase in their let-7 microRNA levels. Lentivirus-mediated overexpression of Lin28 in adult HSCs elevates their self-renewal activity in transplanted irradiated hosts, as does overexpression of Hmga2, a well-established let-7 target that is upregulated in fetal HSCs. Conversely, HSCs from fetal Hmga2−/− mice do not exhibit the heightened self-renewal activity that is characteristic of wild-type fetal HSCs. Interestingly, overexpression of Hmga2 in adult HSCs does not mimic the ability of elevated Lin28 to activate a fetal lymphoid differentiation program. Thus, Lin28b may act as a master regulator of developmentally timed changes in HSC programs with Hmga2 serving as its specific downstream modulator of HSC self-renewal potential. Fetal haematopoietic stem cells (HSCs) display higher self-renewal potential than their adult counterparts. Eaves and colleagues show that adult HSCs express lower levels of Lin28b and higher levels of let-7 miRNA. They demonstrate that Lin28 overexpression, as well as that of Hmga2 (a target of let-7), induces fetal properties in adult HSCs. Conversely, HMGA2 loss in fetal HSCs results in premature induction of adult HSC self-renewal properties.read more
Citations
More filters
Journal ArticleDOI
HMGB1 in Health and Disease
Rui Kang,Ruochan Chen,Qiuhong Zhang,Wen Hou,Sha Wu,Lizhi Cao,Jin Huang,Yan Yu,Xue Gong Fan,Zhengwen Yan,Zhengwen Yan,Xiaofang Sun,Haichao Wang,Qingde Wang,Allan Tsung,Timothy R. Billiar,Herbert J. Zeh,Michael T. Lotze,Daolin Tang +18 more
TL;DR: High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside thecell as the prototypic damage associated molecular pattern molecule (DAMP).
Journal ArticleDOI
Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients.
Tuan Zea Tan,Qing Hao Miow,Yoshio Miki,Tetsuo Noda,Seiichi Mori,Ruby Yun-Ju Huang,Ruby Yun-Ju Huang,Jean Paul Thiery,Jean Paul Thiery +8 more
TL;DR: This universal and quantitative EMT scoring was used to establish an EMT spectrum across various cancers, with good correlation noted between cell lines and tumours, and it is demonstrated that mesenchymal‐like tumours do not always show resistance to chemotherapy.
Journal ArticleDOI
SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma
Soufiane Boumahdi,Gregory Driessens,Gaëlle Lapouge,Sandrine Rorive,Dany Nassar,Marie Le Mercier,Benjamin Delatte,Amélie Caauwe,Sandrine Lenglez,Erwin Nkusi,Sylvain Brohée,Isabelle Salmon,Christine Dubois,Véronique Del Marmol,François Fuks,Benjamin Beck,Cédric Blanpain +16 more
TL;DR: It is demonstrated that SOX2, by marking and regulating the functions of skin tumour-initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours.
Journal ArticleDOI
MicroRNAs as regulatory elements in immune system logic
Arnav Mehta,David Baltimore +1 more
TL;DR: The mechanisms by which several miRNAs influence immune development and buffer normal haematopoietic output are discussed, first at the level of haematic stem cells, then in innate and adaptive immune cells, and the pathological consequences of dysregulation of these mi RNAs are discussed.
Journal ArticleDOI
Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis
Nina Cabezas-Wallscheid,Daniel Klimmeck,Daniel Klimmeck,Jenny Hansson,Daniel B. Lipka,Alejandro Reyes,Qi Wang,Dieter Weichenhan,Amelie Lier,Lisa von Paleske,Simon Renders,Peer Wünsche,Petra Zeisberger,David Brocks,Lei Gu,Lei Gu,Carl Herrmann,Simon Haas,Marieke A.G. Essers,Benedikt Brors,Roland Eils,Wolfgang Huber,Michael D. Milsom,Christoph Plass,Jeroen Krijgsveld,Andreas Trumpp +25 more
TL;DR: An unexpectedly dynamic pattern of transcript isoform regulation is found, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells is found.
References
More filters
Journal ArticleDOI
The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans
Brenda J. Reinhart,Frank J. Slack,Frank J. Slack,Michael Basson,Amy E. Pasquinelli,Bettinger Jc,Ann E. Rougvie,H R Horvitz,Gary Ruvkun +8 more
TL;DR: It is shown that let-7 is a heterochronic switch gene that encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in the 3′ untranslated regions of the heteroch chronic genes lin-14, lin-28, Lin-41, lin -42 and daf-12, indicating that expression of these genes may be directly controlled by let- 7.
Journal ArticleDOI
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
In-Kyung Park,Dalong Qian,Mark J. Kiel,Michael W. Becker,Michael Pihalja,Irving L. Weissman,Sean J. Morrison,Sean J. Morrison,Michael F. Clarke +8 more
TL;DR: The results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs, which are required for haematopoiesis to persist for the lifetime of the animal.
Journal ArticleDOI
ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays.
Yifang Hu,Gordon K. Smyth +1 more
TL;DR: ELDA is a software application for limiting dilution analysis (LDA), with particular attention to the needs of stem cell assays, which is the first limiting dilutions analysis software to provide meaningful confidence intervals for all LDA data sets, including those with 0% or 100% responses.
Journal ArticleDOI
Selective blockade of microRNA processing by Lin28.
TL;DR: The results identify Lin28 as a negative regulator of miRNA biogenesis and suggest that Lin28 may play a central role in blocking miRNA-mediated differentiation in stem cells and in certain cancers.
Journal ArticleDOI
Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
Marina Cavazzana-Calvo,Emmanuel Payen,Olivier Negre,Gary P. Wang,Kathleen M. Hehir,Floriane Fusil,Julian D. Down,Maria Denaro,Troy Brady,Karen A. Westerman,Resy Cavallesco,Beatrix Gillet-Legrand,Laure Caccavelli,Laure Caccavelli,Riccardo Sgarra,Leila Maouche-Chretien,Françoise Bernaudin,Robert Girot,Ronald Dorazio,Geert Jan Mulder,Axel Polack,Arthur Bank,Jean Soulier,Jérôme Larghero,Nabil Kabbara,Bruno Dalle,Bernard Gourmel,Gérard Socié,Stany Chrétien,Stany Chrétien,Nathalie Cartier,Patrick Aubourg,Alain Fischer,Alain Fischer,Kenneth Cornetta,Frédéric Galactéros,Yves Beuzard,Eliane Gluckman,Frederick D. Bushman,Salima Hacein-Bey-Abina,Salima Hacein-Bey-Abina,Philippe Leboulch +41 more
TL;DR: It is shown that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months.
Related Papers (5)
The Lin28/let-7 axis regulates glucose metabolism
Hao Zhu,Ng Shyh-Chang,Ayellet V. Segrè,Ayellet V. Segrè,Gen Shinoda,Samar P. Shah,William S. Einhorn,William S. Einhorn,Ayumu Takeuchi,Jesse M. Engreitz,John P. Hagan,Michael G. Kharas,Michael G. Kharas,Achia Urbach,James E. Thornton,Robinson Triboulet,Richard I. Gregory,David Altshuler,David Altshuler,George Q. Daley +19 more
Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation
Lin28 promotes transformation and is associated with advanced human malignancies
Srinivas R. Viswanathan,John T. Powers,William S. Einhorn,Yujin Hoshida,Tony Ng,Sara Toffanin,Maureen J. O'Sullivan,Jun Lu,Letha A. Phillips,Victoria L Lockhart,Samar P. Shah,Pradeep S. Tanwar,Craig H. Mermel,Rameen Beroukhim,Mohammad Azam,José A. Teixeira,Matthew Meyerson,Timothy P. Hughes,Josep M. Llovet,Jerald P. Radich,Charles G. Mullighan,Todd R. Golub,Poul H. Sorensen,George Q. Daley +23 more