IndraLab

Statements

SCN11A binds KLF1. 29 / 29
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"In contrast to Nan-KLF1, CDA-KLF1 binding sites are mutually exclusive with WT-KLF1 sites; that is, the CDA-KLF1 mutant will not recognize, bind nor activate any of WT-KLF1 targets."
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"The Nan-KLF1 mouse mutant was generated by N -ethyl- N -nitrosourea (ENU) mutagenesis of a C3H/He male mated to a C3H/He healthy wild type female [ xref ]."
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"As a result, both mutations acquire new yet distinct features regarding the transcriptional activity of Nan-KLF1 and CDA-KLF1 variants as compared to WT-KLF1."
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"Therefore, Nan-KLF1 is limited in recognition of some WT-KLF1 target genes, yet also acquires the ability to activate new, ectopic neomorphic genes [ xref , xref ]."
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"The first case concerns murine severe n eonatal an emia (Nan) caused by the Nan-KLF1 mutant."
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"As a result Nan-KLF1 affects mostly the dynamics of progression from primitive to definitive erythropoiesis during mouse development and not the expression of embryonic globins, which stay low (0.3% [ xref ])."
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"In addition, recognition of a novel target DNA sequence by Nan-EKLF leads to ectopic expression of genes not normally expressed in the red cell, yielding a neomorphic phenotype with cellular and systemic consequences xref , xref ."
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"Nan-KLF1 also ectopically binds sites not normally engaged by KLF1 xref , xref ."
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"Identification of the Nan-KLF1 and CDA-KLF1 unique DNA binding sites."
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"Third, we find that for a subset of ectopic targets, gene activation is achieved in Nan/+ only by Nan-EKLF binding to distal enhancers, leading to RNA polymerase II pause-release."
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"Exploring the relationship between aberrant Nan-KLF1 binding and ectopic gene regulation at the genome-wide level we find 205 KLF1 promoter peaks within KLF1 DEGs (28%) and 102 Nan-KLF1 promoter peaks within the Nan-KLF1 DEGs (9%)."
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"Whereas KLF1 only binds G, Nan-KLF1 binds A, G or T at this position in vitro and in vivo ."
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"First, we show that Nan-EKLF limits normal EKLF binding to a subset of its sites."
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"Expression of Dusp7 , Sh3bp1 and Zfp36 gave the highest scores for the neomorphic targets of Nan-KLF1."
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"ChIPseq confirmed ectopic Nan-KLF1 binding to an altered consensus sequence, CCM- NG C-CCN, with the result that >60% of Nan-KLF1 occupied sites do not overlap wild type (WT) KLF1 sites."
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"In the Nan mouse model, the E339D substitution in the second ZnF within the Nan allele, alters Nan-KLF1 binding specificity, resulting in an aberrant transcriptome ( xref )."
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"Such aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use together with intrinsic hypomorphic effects of Nan-KLF1 within erythroid compartment contribute to exacerbation of the severity of neonatal anemia [ xref , xref , xref , xref ]."
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"We propose a model whereby ectopic binding of Nan-KLF1 not only directly drives aberrant gene transcription, but sometimes indirectly disrupts the activity of KLF1-independent erythroid genes or housekeeping genes."
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"Despite this, expression of genes that mutant Nan-KLF1 does not bind is somehow disrupted through an unknown mechanism."
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"Using the in vivo assay, the following binding motifs presented on G-rich strand were determined: for Nan-KLF1 5′-NGG-G C/A N-G/TGG-3′ and for CDA-KLF1 5-NGG-G A/G G-GG/AG-3′ [ xref , xref ]."
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"The mutant CDA-KLF1 and Nan-KLF1 alleles lose all or part of their transcription capacity to activate wild-type KLF1 targets ( xref ) and thus generate a haploinsufficient genetic background in heterozygous organisms."
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"The Nan-KLF1 variant narrows and limits the recognition of WT sites to those having a C in 5th position, but at the same time extends the ability to bind sequences having any nucleotide in the 6th position of the DNA binding motif."
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"Indeed, we previously reported reduced Nan-KLF1 binding to some established KLF1 target sites in vitro by EMSA ( xref )."
28180284
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"Ectopic transcription is activated following ectopic Nan-KLF1 binding to DNA."
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"We found no evidence for Nan-KLF1 binding."
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"Nan-KLF1 binds an altered sequence motif."
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"The hypomorphic model of the biochemical functions of Nan-KLF1 and CDA-KLF1 cannot fully explain the dominant heterozygous phenotype."
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"Second, we find that ectopic binding of Nan-EKLF occurs largely at enhancers and activates transcription through pioneering activity."
36543143
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"Given the large background of molecular, biochemical, and genetic studies of KLF1, of particular interest is to review and compare the mechanisms of action between WT, Nan-KLF1, and CDA-KLF1."
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