A novel Krüppel related factor consisting of only a KRAB domain is expressed in the murine trigeminal ganglion

Nikulina, Karina; Bodeker, MacDara; Warren, John F; Matthews, P. N.; Margolis, Todd P.

doi:10.1016/j.bbrc.2006.07.150

Cited by 3 publications

(2 citation statements)

References 41 publications

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“…ZNF92 (MIM#603974) belongs to the ZNF family of transcription factors, which contains the Kruppel-associated box domain. 33 The ZNF family includes motifs in DNA- and RNA-binding proteins and appears to be involved in many cellular functions, such as DNA recognition, RNA packaging, transcriptional activation, apoptosis regulation, and protein folding and integration. 34 Increasing evidence suggests that genetic variants in ZNFs influence susceptibility to psychiatric disease, especially BD.…”

Section: Discussionmentioning

confidence: 99%

Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

Privitera¹,

Trusso²,

Valentino³

et al. 2023

Brazilian Journal of Psychiatry

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Objective: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as “borderline.” Methods: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the “borderline” individual with moderate anxiety and obsessive-compulsive traits. Results: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a “borderline” phenotype that, if combined with a heterozygous missense variant in ZNF92 , is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. Conclusions: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92 .

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Section: Discussionmentioning

confidence: 99%

Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

Privitera¹,

Trusso²,

Valentino³

et al. 2023

Brazilian Journal of Psychiatry

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“…Some KRAB proteins do consist of only a KRAB domain, e.g. MIF1 (Nikulina et al, 2006), and some are alternatively spliced to generate a KRAB-box only protein, e.g. KRAB-O from the Zfp208 locus (Oh et al, 2005).…”

Section: Krab Zfps Have a Dynamic Nuclear Localisationmentioning

confidence: 99%

KRAB zinc-finger proteins localise to novel KAP1-containing foci that are adjacent to PML nuclear bodies

Briers

Crawford

Bickmore

et al. 2009

Journal of Cell Science

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The KRAB-zinc finger proteins (KRAB-ZFPs) represent a very large, but poorly understood, family of transcriptional regulators in mammals. They are thought to repress transcription via their interaction with KRAB-associated protein 1 (KAP1), which then assembles a complex of chromatin modifiers to lay down histone marks that are associated with inactive chromatin. Studies of KRAB-ZFP/KAP1-mediated gene silencing, using reporter constructs and ectopically expressed proteins, have shown colocalisation of both KAP1 and repressed reporter target genes to domains of constitutive heterochromatin in the nucleus. However, we show here that although KAP1 does indeed become recruited to pericentric heterochromatin during differentiation of mouse embryonic stem (ES) cells, endogenous KRAB-ZFPs do not. Rather, KRAB-ZFPs and KAP1 relocalise to novel nucleoplasmic foci that we have termed KRAB- and KAP1-associated (KAKA) foci. HP1s can also concentrate in these foci and there is a close spatial relationship between KAKA nuclear foci and PML nuclear bodies. Finally, we reveal differential requirements for the recruitment of KAP1 to pericentric heterochromatin and KAKA foci, and suggest that KAKA foci may contain sumoylated KAP1 – the form of the protein that is active in transcriptional repression.

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Epigenetic Gene Silencing by the SRY Protein Is Mediated by a KRAB-O Protein That Recruits the KAP1 Co-repressor Machinery

Peng

Ivanov

et al. 2009

Journal of Biological Chemistry

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The sex determination transcription factor SRY is a cell fatedetermining transcription factor that mediates testis differentiation during embryogenesis. It may function by repressing the ovarian determinant gene, RSPO1, action in the ovarian developmental pathway and activates genes, such as SOX9, important for testis differentiation at the onset of gonadogenesis. Further, altered expression of SRY and related SOX genes contribute to oncogenesis in many human cancers. Little is known of the mechanisms by which SRY regulates its target genes. Recently a KRAB domain protein (KRAB-O) that lacks a zinc finger motif has been demonstrated to interact with SRY and hypothesized to function as an adaptor molecule for SRY by tethering the KAP1-NuRD-SETDB1-HP1 silencing machinery to repress SRY targets. We have critically examined this hypothesis by reconstituting and characterizing SRY-KRAB-O-KAP1 interactions. These recombinant molecules can form a ternary complex by direct and high affinity interactions. The KRAB-O protein can simultaneously bind KAP1 and SRY in a noncompetitive but also noncooperative manner. An extensive mutagenesis analysis suggests that different surfaces on KRAB-O are utilized for these independent interactions. Transcriptional repression by SRY requires binding to KRAB-O, thus bridging to the KAP1 repression machinery. This repression machinery is recruited to SRY target promoters in chromatin templates via SRY. These results suggest that SRY has co-opted the KRAB-O protein to recruit the KAP1 repression machinery to sex determination target genes. Other KRAB domain proteins, which lack a zinc finger DNA-binding motif, may function in similar roles as adaptor proteins for epigenetic gene silencing.

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A novel Krüppel related factor consisting of only a KRAB domain is expressed in the murine trigeminal ganglion

Cited by 3 publications

References 41 publications

Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

KRAB zinc-finger proteins localise to novel KAP1-containing foci that are adjacent to PML nuclear bodies

Epigenetic Gene Silencing by the SRY Protein Is Mediated by a KRAB-O Protein That Recruits the KAP1 Co-repressor Machinery

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