RP58 Associates with Condensed Chromatin and Mediates a Sequence-specific Transcriptional Repression

Aoki, Katsunori; Meng, Guowang; Suzuki, Kenji; Takashi, Tohru; Kameoka, Yosuke; Nakahara, Kazuhiko; Ishida, Ryôhei; Kasai, Masataka

doi:10.1074/jbc.273.41.26698

Cited by 83 publications

(87 citation statements)

References 35 publications

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“…A number of mammalian BTB/ POZ-zinc finger factors are expressed in the central nervous system (52)(53)(54)(55)(56)(57), but the functional significance of this expression is not clear. In addition, the BTB/POZ domain factors BCL-6/LAZ3 and PLZF have been implicated in human malignancies involving chromosomal translocations (15,58,59).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Two Novel Nuclear BTB/POZ Domain Zinc Finger Isoforms

Mitchelmore¹,

Kjærulff²,

Pedersen³

et al. 2002

Journal of Biological Chemistry

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BTB/POZ (broad complex tramtrack bric-a-brac/poxvirus and zinc finger) zinc finger factors are a class of nuclear DNA-binding proteins involved in development, chromatin remodeling, and cancer. However, BTB/POZ domain zinc finger factors linked to development of the mammalian cerebral cortex, cerebellum, and macroglia have not been described previously. We report here the isolation and characterization of two novel nuclear BTB/POZ domain zinc finger isoforms, designated HOF L and HOF S , that are specifically expressed in early hippocampal neurons, cerebellar granule cells, and gliogenic progenitors as well as in differentiated glia. During embryonic development of the murine cerebral cortex, HOF expression is restricted to the hippocampal subdivision. Expression coincides with early differentiation of presumptive CA1 and CA3 pyramidal neurons and dentate gyrus granule cells, with a sharp decline in expression at the CA1/subicular border. By using bromodeoxyuridine labeling and immunohistochemistry, we show that HOF expression coincides with immature non-dividing cells and is down-regulated in differentiated cells, suggesting a role for HOF in hippocampal neurogenesis. Consistent with the postulated role of the POZ domain as a site for protein-protein interactions, both HOF isoforms are able to dimerize. The HOF zinc fingers bind specifically to the binding site for the related promyelocytic leukemia zinc finger protein as well as to a newly identified DNA sequence.

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Section: Discussionmentioning

confidence: 99%

Characterization of Two Novel Nuclear BTB/POZ Domain Zinc Finger Isoforms

Mitchelmore¹,

Kjærulff²,

Pedersen³

et al. 2002

Journal of Biological Chemistry

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“…A putative neuroD1 promoter region (1663 bp) containing one RP58 potential binding site 14 was cloned from mouse genomic DNA using the two primers as shown in Figure 4j (forward primer: CCACAATGCCTTGCTTTTC and reverse primer: GGACACCTTGCCTTCTGC). The fragment was inserted into the pGL3-basic vector.…”

Section: Methodsmentioning

confidence: 99%

“…As pax6, ngn2 and neuroD1 encode essential sequential functions for neurogenesis (e.g., Hevner, 7 Hevner et al 8 and Miyata et al 27 ), we investigated the possibility that RP58 regulates the number of neurons in the developing cerebral cortex by directly regulating these key neurogenic determinants. Putative conserved consensus RP58-binding sites 14 were detected in the proximal regulatory regions of ngn2 and neuroD1 (Supplementary Figure 11). Chromatin immunoprecipitation (ChIP) analyses using an anti-RP58 antibody 13 were thus performed for these two genes first on whole cortices and then on sorted cells from control cortices taken at the same stage.…”

Section: Loss Of Rp58 Causes Coherent and Inappropriately Persistent mentioning

confidence: 99%

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RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

et al. 2011

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Although neurogenic pathways have been described in the developing neocortex, less is known about mechanisms ensuring correct neuronal differentiation thus also preventing tumor growth. We have shown that RP58 (aka zfp238 or znf238) is highly expressed in differentiating neurons, that its expression is lost or diminished in brain tumors, and that its reintroduction blocks their proliferation. Mice with loss of RP58 die at birth with neocortical defects. Using a novel conditional RP58 allele here we show that its CNS-specific loss yields a novel postnatal phenotype: microencephaly, agenesis of the corpus callosum and cerebellar hypoplasia that resembles the chr1qter deletion microcephaly syndrome in human. RP58 mutant brains maintain precursor pools but have reduced neuronal and increased glial differentiation. Well-timed downregulation of pax6, ngn2 and neuroD1 depends on RP58 mediated transcriptional repression, ngn2 and neuroD1 being direct targets. Thus, RP58 may act to favor neuronal differentiation and brain growth by coherently repressing multiple proneurogenic genes in a timely manner. The cerebral cortex undergoes rapid expansion during embryogenesis, when neuronal layers are formed. Two main types of precursors exist in the developing neocortex: multipotent radial glial stem/progenitor cells (RGCs) in the ventricular zone (VZ) and derived intermediate neurogenic progenitors (INPs) in the subventricular zone (SVZ). 1-3 INPs divide 1-2 times and only give rise to neurons, with regulation of their number proposed to contribute to cortical expansion. [1][2][3][4][5][6] Molecularly, a sequence of key transcription factors, Pax6-4Ngn2-4Tbr2-4NeuroD1-4Tbr1, promotes cortical neurogenesis. 7 Among these, Ngn2 is required for transition from early Pax6 þ radial glia to Tbr2 þ INPs, as well as for expansion of INPs, whereas NeuroD1 is expressed in INPs and early-differentiating neurons. 7,8 How their sequential timed expression is regulated to promote the development of normal-sized cortices is unknown.The development of human microcephaly likely results from abnormal cortical precursor behavior. Interestingly, deletion of the distal end of human chromosome-1q is linked to microcephaly with agenesis of the corpus callosum (e.g. 9-11), and a critical region contains only a handful of genes, including RP58. 9-12 RP58, also known as ZNF238, 13 encodes a transcription factor with a BTB/POZ and four zincfinger domains 14 that is highly conserved (495%) between humans and mice, suggesting conserved functions.Previous work has shown that RP58 is expressed in mouse brain precursors and neurons, 15 and that its complete loss leads to defects in cortical and hippocampal development. 16 Critically, perinatal death of conventional knockout (KO) mice 16 precludes analyses in postnatal stages. Furthermore, the reported defects in cell-cycle exit, and in Pax6 þ and Tbr2 þ populations, were deduced from analyses at late corticogenesis stages after embryonic day (E) 16.5, precluding any conclusions on early defects and not provi...

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“…19 ZNF238 is a POZ/zinc finger transcriptional repressor gene. 20 Mice with targeted knock out of ZNF238 display severe hypoplasia of the cerebral cortex and the hippocampus, along with increased apoptosis of progenitors in the ventricular zone. 21 These functional data and the genotypephenotype correlation in our patients implicate deletion of CEP170 and/or ZNF238 as the cause for CCAs.…”

Section: Deletion Of 1q43-q44 Scs Nagamani Et Almentioning

confidence: 99%

Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43–q44

et al. 2011

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Submicroscopic deletions involving chromosome 1q43-q44 result in cognitive impairment, microcephaly, growth restriction, dysmorphic features, and variable involvement of other organ systems. A consistently observed feature in patients with this deletion are the corpus callosal abnormalities (CCAs), ranging from thinning and hypoplasia to complete agenesis. Previous studies attempting to delineate the critical region for CCAs have yielded inconsistent results. We conducted a detailed clinical and molecular characterization of seven patients with deletions of chromosome 1q43-q44. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. Four patients had CCAs, and shared the smallest region of overlap that contains only three protein coding genes, CEP170, SDCCAG8, and ZNF238. One patient with a small deletion involving SDCCAG8 and AKT3, and another patient with an intragenic deletion of AKT3 did not have any CCA, implying that the loss of these two genes is unlikely to be the cause of CCA. CEP170 is expressed extensively in the brain, and encodes for a protein that is a component of the centrosomal complex. ZNF238 is involved in control of neuronal progenitor cells and survival of cortical neurons. Our results rule out the involvement of AKT3, and implicate CEP170 and/or ZNF238 as novel genes causative for CCA in patients with a terminal 1q deletion.

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RP58 Associates with Condensed Chromatin and Mediates a Sequence-specific Transcriptional Repression

Cited by 83 publications

References 35 publications

Characterization of Two Novel Nuclear BTB/POZ Domain Zinc Finger Isoforms

Characterization of Two Novel Nuclear BTB/POZ Domain Zinc Finger Isoforms

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43–q44

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