scholarly journals Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

2021 ◽  
Author(s):  
Deepthi Sudarshan ◽  
Nikita Avvakumov ◽  
Marie-Eve Lalonde ◽  
Nader Alerasool ◽  
Karine Jacquet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Repression ◽  
Chimeric Protein ◽  
Chromosomal Translocations ◽  
Transcription Activator ◽  
Polycomb Repressive Complex 2 ◽  
Aberrant Gene Expression ◽  
Hoxd Cluster ◽  
Frame Fusion ◽  
Aberrant Gene

Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with Endometrial Stromal Sarcomas (ESS) and Ossifying FibroMyxoid Tumors (OFMT) leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a co-activator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a mega-complex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome. These are linked to aberrant gene expression, in particular over an entire topologically-associated domain including part of the HOXD cluster. Furthermore, we show that JAZF1, implicated with PRC2 components in the most frequent translocations in ESS, is a potent transcription activator that physically associates with NuA4/TIP60. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas employ the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes leading to mislocalization of histone marks and aberrant polycomb target gene expression.

AML displays increased CTCF occupancy associated with aberrant gene expression and transcription factor binding

Blood ◽  
2020 ◽  
Vol 136 (3) ◽  
pp. 339-352 ◽  
Author(s):  
Huthayfa Mujahed ◽  
Sophia Miliara ◽  
Anne Neddermeyer ◽  
Sofia Bengtzén ◽  
Christer Nilsson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcriptional Repression ◽  
Gene Expression Pattern ◽  
K562 Cells ◽  
Ctcf Binding ◽  
Promoter Regions ◽  
Aberrant Gene Expression ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Aberrant Gene

Abstract CCTC-binding factor (CTCF) is a key regulator of gene expression through organization of the chromatin structure. Still, it is unclear how CTCF binding is perturbed in leukemia or in cancer in general. We studied CTCF binding by chromatin immunoprecipitation sequencing in cells from patients with acute myeloid leukemia (AML) and in normal bone marrow (NBM) in the context of gene expression, DNA methylation, and azacitidine exposure. CTCF binding was increased in AML compared with NBM. Aberrant CTCF binding was enriched for motifs for key myeloid transcription factors such as CEBPA, PU.1, and RUNX1. AML with TET2 mutations was characterized by a particularly strong gain of CTCF binding, highly enriched for gain in promoter regions, while AML in general was enriched for changes at enhancers. There was a strong anticorrelation between CTCF binding and DNA methylation. Gain of CTCF occupancy was associated with increased gene expression; however, the genomic location (promoter vs distal regions) and enrichment of motifs (for repressing vs activating cofactors) were decisive for the gene expression pattern. Knockdown of CTCF in K562 cells caused loss of CTCF binding and transcriptional repression of genes with changed CTCF binding in AML, as well as loss of RUNX1 binding at RUNX1/CTCF-binding sites. In addition, CTCF knockdown caused increased differentiation. Azacitidine exposure caused major changes in CTCF occupancy in AML patient cells, partly by restoring a CTCF-binding pattern similar to NBM. We conclude that AML displays an aberrant increase in CTCF occupancy that targets key genes for AML development and impacts gene expression.

scholarly journals Publisher Correction to: C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Tatsuya Ozawa ◽  
Syuzo Kaneko ◽  
Frank Szulzewsky ◽  
Zhiwei Qiao ◽  
Mutsumi Takadera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epigenetic Regulation ◽  
Aberrant Gene Expression ◽  
Aberrant Gene

An amendment to this paper has been published and can be accessed via the original article.

scholarly journals Transcriptome analysis identified aberrant gene expression in pollen developmental pathways leading to CGMS in cotton (Gossypium hirsutum L.)

PLoS ONE ◽  
2019 ◽  
Vol 14 (6) ◽  
pp. e0218381 ◽  
Author(s):  
Rasmieh Hamid ◽  
Hassan Marashi ◽  
Rukam S. Tomar ◽  
Saeid Malekzadeh Shafaroudi ◽  
Pritesh H. Sabara
Keyword(s):  
Gene Expression ◽  
Gossypium Hirsutum ◽  
Transcriptome Analysis ◽  
Developmental Pathways ◽  
Gossypium Hirsutum L ◽  
Aberrant Gene Expression ◽  
Aberrant Gene

Aberrant gene expression in cultured mammalian bone cells demonstrates an osteoblast defect in osteopetrosis

1994 ◽  
Vol 55 (3) ◽  
pp. 366-372 ◽  
Author(s):  
M. E. Jackson ◽  
V. Shalhoub ◽  
J. B. Lian ◽  
G. S. Stein ◽  
S. C. Marks
Keyword(s):  
Gene Expression ◽  
Bone Cells ◽  
Aberrant Gene Expression ◽  
Aberrant Gene ◽  
Mammalian Bone

scholarly journals Lineage promiscuity in hemopoietic differentiation and leukemia

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 1-11 ◽  
Author(s):  
MF Greaves ◽  
LC Chan ◽  
AJ Furley ◽  
SM Watt ◽  
HV Molgaard
Keyword(s):  
Gene Expression ◽  
Cell Receptor ◽  
Leukemic Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Aberrant Gene Expression ◽  
Lineage Infidelity ◽  
T Cell Receptor Genes ◽  
Bona Fide ◽  
Aberrant Gene ◽  
Ig Heavy Chain

An increasing number of reports document instances in which individual leukemic cells coexpress markers normally believed to be restricted to a single lineage. This has been interpreted by McCulloch and colleagues as aberrant programming or lineage infidelity and contrasts with earlier suggestions that lineage fidelity of gene expression was usually maintained in leukemia. We argue that several examples of infidelity are suspect on technical grounds, whereas others are bona fide and require explanation, eg, partial rearrangements and expression of Ig heavy-chain and/or T cell receptor genes in inappropriate cells and terminal deoxynucleotidyl transferase in leukemic myeloblasts. Individual examples of truly aberrant gene expression may well occur in leukemia but with insufficient regularity to be of general significance. We suggest that verifiable and consistent examples of apparent lineage infidelity do not reflect genetic misprogramming but rather the existence of a transient phase of limited promiscuity of gene expression occurring in normal biopotential or multipotential progenitors and able to be preserved as a relic in leukemic blast cell populations that are in maturation arrest. This alternative explanation has interesting implications for mechanisms of hematopoietic differentiation and leads to some testable predictions.

scholarly journals FBXO11-Mediated Proteolysis of BAHD1 Relieves PRC2-dependent Transcriptional Repression in Erythropoiesis

Blood ◽  
2020 ◽  
Author(s):  
Peng Xu ◽  
Daniel C. Scott ◽  
Beisi Xu ◽  
Yu Yao ◽  
Ruopeng Feng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ubiquitin Ligase ◽  
Transcriptional Repression ◽  
E3 Ubiquitin Ligase ◽  
Histone Mark ◽  
Developmentally Delayed ◽  
Hematopoietic Development ◽  
Polycomb Repressive Complex 2 ◽  
Stem And Progenitor Cells ◽  
Erythroid Maturation

The histone mark H3K27me3 and its reader/writer Polycomb repressive complex 2 (PRC2) mediate widespread transcriptional repression in stem and progenitor cells. Mechanisms that regulate this activity are critical for hematopoietic development but poorly understood. Here we show that the E3 ubiquitin ligase FBXO11 relieves PRC2-mediated repression during erythroid maturation by targeting its newly identified substrate BAHD1, an H3K27me3 reader that recruits transcriptional co-repressors. Erythroblasts lacking FBXO11 are developmentally delayed, with reduced expression of maturation-associated genes, most of which harbor bivalent histone marks (activating H3K4me3 and repressive H3K27me3), bind BAHD1, and fail to recruit the erythroid transcription factor GATA1. The BAHD1 complex interacts physically with PRC2 and depletion of either component restores FBXO11-deficient erythroid gene expression. Our studies identify BAHD1 as a novel effector of PRC2-mediated repression and reveal how a single E3 ubiquitin ligase eliminates PRC2 repression at developmentally poised bivalent genes during erythropoiesis.

Sign in / Sign up

Export Citation Format

Share Document