Publications
138 results found
Blevins R, Bruno L, Carroll T, et al., 2015, microRNAs regulate cell-to-cell variability of endogenous target gene expression in developing mouse thymocytes, Plos Genetics, Vol: 11, Pages: 1-19, ISSN: 1553-7404
The development and homeostasis of multicellular organisms relies on gene regulationwithin individual constituent cells. Gene regulatory circuits that increase the robustness ofgene expression frequently incorporate microRNAs as post-transcriptional regulators.Computational approaches, synthetic gene circuits and observations in model organismspredict that the co-regulation of microRNAs and their target mRNAs can reduce cell-to-cellvariability in the expression of target genes. However, whether microRNAs directly regulatevariability of endogenous gene expression remains to be tested in mammalian cells. Herewe use quantitative flow cytometry to show that microRNAs impact on cell-to-cell variabilityof protein expression in developing mouse thymocytes. We find two distinct mechanismsthat control variation in the activation-induced expression of the microRNA target CD69.First, the expression of miR-17 and miR-20a, two members of the miR-17-92 cluster, is coregulatedwith the target mRNA Cd69 to form an activation-induced incoherent feed-forwardloop. Another microRNA, miR-181a, acts at least in part upstream of the target mRNA Cd69to modulate cellular responses to activation. The ability of microRNAs to render gene expressionmore uniform across mammalian cell populations may be important for normal developmentand for disease.
Ing-Simmons E, Seitan VC, Faure AJ, et al., 2015, Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin, Genome Research, Vol: 25, Pages: 504-513, ISSN: 1054-9803
In addition to mediating sister chromatid cohesion during the cell cycle, the cohesin complex associates with CTCF and with active gene regulatory elements to form long-range interactions between its binding sites. Genome-wide chromosome conformation capture had shown that cohesin's main role in interphase genome organization is in mediating interactions within architectural chromosome compartments, rather than specifying compartments per se. However, it remains unclear how cohesin-mediated interactions contribute to the regulation of gene expression. We have found that the binding of CTCF and cohesin is highly enriched at enhancers and in particular at enhancer arrays or “super-enhancers” in mouse thymocytes. Using local and global chromosome conformation capture, we demonstrate that enhancer elements associate not just in linear sequence, but also in 3D, and that spatial enhancer clustering is facilitated by cohesin. The conditional deletion of cohesin from noncycling thymocytes preserved enhancer position, H3K27ac, H4K4me1, and enhancer transcription, but weakened interactions between enhancers. Interestingly, ∼50% of deregulated genes reside in the vicinity of enhancer elements, suggesting that cohesin regulates gene expression through spatial clustering of enhancer elements. We propose a model for cohesin-dependent gene regulation in which spatial clustering of enhancer elements acts as a unified mechanism for both enhancer-promoter “connections” and “insulation.”
Lavagnolli T, Gupta P, Hörmanseder E, et al., 2015, Initiation and maintenance of pluripotency gene expression in the absence of cohesin., Genes Dev, Vol: 29, Pages: 23-38
Cohesin is implicated in establishing and maintaining pluripotency. Whether this is because of essential cohesin functions in the cell cycle or in gene regulation is unknown. Here we tested cohesin's contribution to reprogramming in systems that reactivate the expression of pluripotency genes in the absence of proliferation (embryonic stem [ES] cell heterokaryons) or DNA replication (nuclear transfer). Contrary to expectations, cohesin depletion enhanced the ability of ES cells to initiate somatic cell reprogramming in heterokaryons. This was explained by increased c-Myc (Myc) expression in cohesin-depleted ES cells, which promoted DNA replication-dependent reprogramming of somatic fusion partners. In contrast, cohesin-depleted somatic cells were poorly reprogrammed in heterokaryons, due in part to defective DNA replication. Pluripotency gene induction was rescued by Myc, which restored DNA replication, and by nuclear transfer, where reprogramming does not require DNA replication. These results redefine cohesin's role in pluripotency and reveal a novel function for Myc in promoting the replication-dependent reprogramming of somatic nuclei.
Marcais A, Blevins R, Graumann J, et al., 2014, microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells, Journal of Experimental Medicine, Vol: 211, Pages: 2281-2295, ISSN: 0022-1007
T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation–independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.
Piccolo FM, Fisher AG, 2014, Getting rid of DNA methylation, TRENDS IN CELL BIOLOGY, Vol: 24, Pages: 136-143, ISSN: 0962-8924
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- Citations: 57
Seitan VC, Faure AJ, Zhan Y, et al., 2013, Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments, GENOME RESEARCH, Vol: 23, Pages: 2066-2077, ISSN: 1088-9051
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- Citations: 234
Brown KE, Bagci H, Soza-Ried J, et al., 2013, Atypical heterochromatin organization and replication are rapidly acquired by somatic cells following fusion-mediated reprogramming by mouse ESCs, CELL CYCLE, Vol: 12, Pages: 3253-3261, ISSN: 1538-4101
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- Citations: 6
Bagci H, Fisher AG, 2013, DNA Demethylation in Pluripotency and Reprogramming: The Role of Tet Proteins and Cell Division, CELL STEM CELL, Vol: 13, Pages: 265-269, ISSN: 1934-5909
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- Citations: 55
Piccolo FM, Bagci H, Brown KE, et al., 2013, Different Roles for Tet1 and Tet2 Proteins in Reprogramming-Mediated Erasure of Imprints Induced by EGC Fusion, MOLECULAR CELL, Vol: 49, Pages: 1023-1033, ISSN: 1097-2765
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- Citations: 81
Piccolo FM, Bagci H, Brown KE, et al., 2013, Different Roles for Tet1 and Tet2 Proteins in Reprogramming-Mediated Erasure of Imprints Induced by EGC Fusion (vol 49, pg 1023, 2013), MOLECULAR CELL, Vol: 49, Pages: 1176-1176, ISSN: 1097-2765
Ferreiros-Vidal I, Carroll T, Taylor B, et al., 2013, Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation, BLOOD, Vol: 121, Pages: 1769-1782, ISSN: 0006-4971
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- Citations: 82
Cantone I, Fisher AG, 2013, Epigenetic programming and reprogramming during development, NATURE STRUCTURAL & MOLECULAR BIOLOGY, Vol: 20, Pages: 282-289, ISSN: 1545-9993
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- Citations: 306
Tsubouchi T, Soza-Ried J, Brown K, et al., 2013, DNA Synthesis Is Required for Reprogramming Mediated by Stem Cell Fusion, CELL, Vol: 152, Pages: 873-883, ISSN: 0092-8674
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- Citations: 60
Tsubouchi T, Fisher AG, 2013, Reprogramming and the Pluripotent Stem Cell Cycle, EPIGENETICS AND DEVELOPMENT, Editors: Heard, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 223-241, ISBN: 978-0-12-416027-9
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- Citations: 13
Fisher AG, Brockdorff N, 2012, Epigenetic memory and parliamentary privilege combine to evoke discussions on inheritance, DEVELOPMENT, Vol: 139, Pages: 3891-3896, ISSN: 0950-1991
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- Citations: 4
Soza-Ried J, Fisher AG, 2012, Reprogramming somatic cells towards pluripotency by cellular fusion, CURRENT OPINION IN GENETICS & DEVELOPMENT, Vol: 22, Pages: 459-465, ISSN: 0959-437X
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- Citations: 21
Merkenschlager M, Seitan V, Tachibana K, et al., 2012, Cohesin regulates T cell receptor rearrangement and thymocyte differentiation, 1st Biennial Symposium on Regulatory T Cells and T Helper Cells, Publisher: WILEY-BLACKWELL, Pages: 3-3, ISSN: 0019-2805
Seitan V, Tachibana K, Hao B, et al., 2011, How cohesin regulates gene expression and differentiation in non-dividing mammalian cells, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 21-21, ISSN: 0019-2805
Seitan VC, Hao B, Tachibana-Konwalski K, et al., 2011, A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation, Nature, Vol: 476, Pages: 467-U126, ISSN: 0028-0836
Cohesin enables post-replicative DNA repair and chromosome segregation by holding sister chromatids together from the time of DNA replication in S phase until mitosis1. There is growing evidence that cohesin also forms long-range chromosomal cis-interactions2,3,4 and may regulate gene expression2,3,4,5,6,7,8,9,10 in association with CTCF8,9, mediator4 or tissue-specific transcription factors10. Human cohesinopathies such as Cornelia de Lange syndrome are thought to result from impaired non-canonical cohesin functions7, but a clear distinction between the cell-division-related and cell-division-independent functions of cohesion—as exemplified in Drosophila11,12,13—has not been demonstrated in vertebrate systems. To address this, here we deleted the cohesin locus Rad21 in mouse thymocytes at a time in development when these cells stop cycling and rearrange their T-cell receptor (TCR) α locus (Tcra). Rad21-deficient thymocytes had a normal lifespan and retained the ability to differentiate, albeit with reduced efficiency. Loss of Rad21 led to defective chromatin architecture at the Tcra locus, where cohesion-binding sites flank the TEA promoter and the Eα enhancer, and demarcate Tcra from interspersed Tcrd elements and neighbouring housekeeping genes. Cohesin was required for long-range promoter–enhancer interactions, Tcra transcription, H3K4me3 histone modifications that recruit the recombination machinery14,15 and Tcra rearrangement. Provision of pre-rearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome4,8,9,10, defective Tcra rearrangement was limiting for the differentiation of cohesin-deficient thymocytes. These findings firmly establish a cell-division-independent role for cohesin in Tcra locus rearrangement and provide a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammali
Piccolo FM, Pereira CF, Cantone I, et al., 2011, Using heterokaryons to understand pluripotency and reprogramming, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 366, Pages: 2260-2265, ISSN: 0962-8436
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- Citations: 23
Fisher CL, Fisher AG, 2011, Chromatin states in pluripotent, differentiated, and reprogrammed cells, CURRENT OPINION IN GENETICS & DEVELOPMENT, Vol: 21, Pages: 140-146, ISSN: 0959-437X
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- Citations: 133
Cantone I, Fisher AG, 2011, Unraveling Epigenetic Landscapes: The Enigma of Enhancers, CELL STEM CELL, Vol: 8, Pages: 128-129, ISSN: 1934-5909
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- Citations: 2
Landeira D, Fisher AG, 2011, Inactive yet indispensable: the tale of Jarid2, TRENDS IN CELL BIOLOGY, Vol: 21, Pages: 74-80, ISSN: 0962-8924
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- Citations: 71
Mazzarella L, Jorgensen HF, Soza-Ried J, et al., 2011, Embryonic stem cell-derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression, BLOOD, Vol: 117, Pages: 83-87, ISSN: 0006-4971
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- Citations: 13
Jorgensen HF, Fisher AG, 2010, Can controversies be put to REST?, NATURE, Vol: 467, Pages: E3-E4, ISSN: 0028-0836
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- Citations: 9
Liber D, Domaschenz R, Holmqvist P-H, et al., 2010, Epigenetic Priming of a Pre-B Cell-Specific Enhancer through Binding of Sox2 and Foxd3 at the ESC Stage, CELL STEM CELL, Vol: 7, Pages: 114-126, ISSN: 1934-5909
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- Citations: 66
Schnetz MP, Handoko L, Akhtar-Zaidi B, et al., 2010, CHD7 Targets Active Gene Enhancer Elements to Modulate ES Cell- Specific Gene Expression, PLOS GENETICS, Vol: 6, ISSN: 1553-7404
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- Citations: 180
Hadjur S, Williams L, Mira H, et al., 2010, Cohesins Contribute to Long-Range Chromosomal cis-Interactions, 11th International Congress on Cleft Lip and Palate and Related Craniofacial Anomalies, Publisher: WILEY-LISS, Pages: 1634-1634, ISSN: 1552-4825
Fisher AG, Merkenschlager M, 2010, Fresh powder on Waddington's slopes, EMBO REPORTS, Vol: 11, Pages: 490-492, ISSN: 1469-221X
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- Citations: 3
Kanhere A, Viiri K, Araujo CC, et al., 2010, Short RNAs Are Transcribed from Repressed Polycomb Target Genes and Interact with Polycomb Repressive Complex-2, MOLECULAR CELL, Vol: 38, Pages: 675-688, ISSN: 1097-2765
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- Citations: 295
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