KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands

Farcas, Anca M.; Blackledge, Neil P.; Sudbery, Ian; Long, Hannah K.; McGouran, Joanna F.; Rose, Nathan R.; Lee, Sheena; Sims, David; Cerase, Andrea; Sheahan, Thomas W.; Koseki, Haruhiko; Brockdorff, Neil; Ponting, Chris P.; Kessler, Benedikt M.; Klose, Robert J.

doi:10.7554/elife.00205

Cited by 427 publications

(545 citation statements)

References 85 publications

Supporting

Mentioning

510

Contrasting

Unclassified

Order By: Relevance

“…13 The high heterogeneity of PRC1 complexes is thought to allow a combinatorial assembly of multiple subunits to integrate additional biochemical activities including readers for other histone modifications-such as HP1s or the Malignant Brain Tumor (MBT) family members 26 -as well as histone modifiers-such as HDACs. 11 In the mouse embryo, PcG proteins support 'facultative' heterochromatin establishment in the male pronucleus 3,25,28 , and a mutation in K27 within H3.3, the main histone variant incorporated in the male pronucleus, results in developmental arrest and heterochromatin defects. 27 In addition, the combined deletion of both RING1 subunits, RING1A and RING1B, results in developmental arrest before the 2-cell stage due to defective regulation of the transcriptional program of the oocyte.…”

Section: Introductionmentioning

confidence: 99%

Characterization of non-canonical Polycomb Repressive Complex 1 subunits during early mouse embryogenesis

Eid

Torres-Padilla

2016

Epigenetics

View full text Add to dashboard Cite

An intense period of chromatin remodeling takes place after fertilization in mammals, which is thought necessary for epigenetic reprogramming to start a new developmental program. While much attention has been given to the role of Polycomb Repressive Complex 2 (PRC2) and to canonical PRC1 complexes during this process, little is known as to whether there is any contribution of non-canonical PRC1 in shaping the chromatin landscape after fertilization. Here, we first describe in detail the temporal dynamics and abundance of H2A ubiquitylation (H2AK119ub), a histone modification catalyzed by PRC1, during preimplantation mouse development. In addition, we have analyzed the presence of the 2 characteristic subunits of non-canonical PRC1 complexes, RYBP and its homolog YAF-2. Our results indicate that H2AK119ub is inherited from the sperm, rapidly removed from the paternal chromatin after fertilization, but detected again prior to the first mitosis, suggesting that PRC1 activity occurs as early as the zygotic stage. RYBP and YAF-2, together with the non-canonical subunit L3MBTL2, are all present during preimplantation development but show different temporal dynamics. While RYBP is absent in the zygote, it is strongly induced from the 4-cell stage onwards. YAF-2 is inherited maternally and localizes to the pericentromeric regions in the zygote, is strongly induced between the 2-and 4-cell stages but then remains weak to undetectable subsequently. All together, our data suggest that non-canonical PRC1 is active during pre-implantation development and should be regarded as an additional component during epigenetic reprogramming and in the establishment of cellular plasticity of the early embryo.

show abstract

Section: Introductionmentioning

confidence: 99%

Characterization of non-canonical Polycomb Repressive Complex 1 subunits during early mouse embryogenesis

Eid

Torres-Padilla

2016

Epigenetics

View full text Add to dashboard Cite

show abstract

“…6,8 Fbxl10 was also recently reported to mediate the monoubiquitination of the histone H2A at lysine 119 as a component of noncanonical polycomb-repressive complex 1 in embryonic stem (ES) cells. 9,10 Several lines of evidence have so far suggested that Fbxl10 is a tumor accelerator. Overexpression of Fbxl10 in fibroblasts inhibited cellular senescence by repressing p16ink4a-p19Arf and p15ink4b loci in mouse as well as Rb and p53 loci in humans, resulting in cellular immortalization.…”

mentioning

confidence: 99%

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Ueda¹,

Nagamachi

Takubo

et al. 2015

Blood

View full text Add to dashboard Cite

• Fbxl10 is a bona fide oncogene in vivo. • Fbxl10 overexpression inHSCs induces mitochondrial metabolic activation and enhanced expression of Nsg2.We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for 27/7q2 syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10 Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. (Blood. 2015;125(22):3437-3446) IntroductionAppropriate patterns of epigenetic alterations in histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases such as cancer. 1 We previously generated knockout mice for Samd9L (which was cloned as a candidate gene for the 27/7q2 syndrome frequently that is observed in myelodysplastic syndrome and acute leukemia patients) and demonstrated that mice deficient in Samd9L developed leukemia after a long latent period. 2 In addition, retroviral insertional mutagenesis revealed that the onset of the disease was highly accelerated with upregulation of F-box and leucine-rich repeat protein 10 (Fbxl10) or ectopic virus integration 1 (Evi1). 2 Clinically, an elevated expression of Fbxl10 is observed in patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL), seminoma, and pancreatic ductal adenocarcinoma. [3][4][5][6] These findings prompted us to further investigate the role of Fbxl10 in leukemia development in vivo.Fbxl10 belongs to the JmjC domain-containing histone demethylases, and contains an N-terminal JmjC domain, followed by a CXXC zinc finger domain, a plant homeodomain finger, an F-box, and 8 leucine-rich repeats. 7 Fbxl10 preferentially demethylates the dimethylation of histone H3 at lysine 36 (H3K36me2), but not H3K36me1 and H3K36me3. 6,8 Fbxl10 was also recently reported to mediate the monoubiquitination of t...

show abstract

“…Biochemical analyses identified BCOR as a complex comprising ring finger protein 2 (RFN2)/ring finger protein 1B (RING1B), polycomb group ring finger 1 (PCGF1)/nervous system polycomb 1 (NSPC1), lysine-specific demethylase 2B (KDM2B)/ F-box and leucine-rich repeat protein 10 (FBXL10), BCOR-like 1 (BCORL1), Ring 1 and YY1 binding protein (RYBP), YY1-associated factor 2 (YAF2), and S phase kinaseassociated protein 1 (SKP1; refs. [2][3][4]. The BCOR complex components are similar to the polycomb repressive complex 1 (PRC1) components ( Fig.…”

Section: The Bcl6 Corepressor Complex As a Repressive Transcriptionamentioning

confidence: 91%

“…KDM2B recruits the BCOR complex to nonmethylated CpG islands (CGI) through the ZF-CxxC DNA-binding domain of KDM2B (Fig. 1), not through H3K27me3-dependent targeting mechanisms (4,7). In addition, ChIP-seq analysis of embryonic stem (ES) cells revealed that KDM2B was enriched near transcription start sites, including Hox gene loci (7).…”

Section: The Bcor Complex Is a Distinct Subtype Of Prc1mentioning

confidence: 99%

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

Yamamoto

Abe

Emi

2014

Molecular Cancer Research

View full text Add to dashboard Cite

The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCORlike 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 479-84. Ó2014 AACR. IntroductionA major cause of developmental diseases and cancers is the dysregulation of proper transcriptional control, a process that is directly regulated by transcription factors, coactivators, and corepressors. Till date, several hundred transcriptional coregulators have been reported in the literature. Recently, the increased use of massively parallel sequencing techniques has expanded our knowledge on the induction of congenital diseases and cancers caused by specific gene mutations.

show abstract

KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands

Cited by 427 publications

References 85 publications

Characterization of non-canonical Polycomb Repressive Complex 1 subunits during early mouse embryogenesis

Characterization of non-canonical Polycomb Repressive Complex 1 subunits during early mouse embryogenesis

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

Contact Info

Product

Resources

About