DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins

Patel, Anamika; Yang, Peng; Tinkham, Matthew; Pradhan, Mihika; Sun, Miao‐Kun; Wang, Yixuan; Hoang, Don; Wolf, Gernot; Horton, J.R.; Zhang, Xing; Macfarlan, Todd S.; Cheng, Xiaodong

doi:10.1016/j.cell.2018.02.058

Cited by 54 publications

(45 citation statements)

References 71 publications

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“…Unexpectedly, Q419 of ZF5 bridges between two base pairs, spanning two thymine bases of the top strand (Figure 4F; PDB ID: 6ML3) or between guanine-2 and adenine-3 from opposite strands (Figure 4G; PDB ID: 6ML4). The unusual one-residue spanning two-base pair recognition has recently been observed in ZFP568 (43), where a histidine spanning two base pairs. The expansion allowed the single unit of ZF4 to recognize 4-bp.…”

Section: Resultsmentioning

confidence: 83%

Structural basis of specific DNA binding by the transcription factor ZBTB24

Ren

Hardikar

Horton

et al. 2019

Nucleic Acids Research

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ZBTB24, encoding a protein of the ZBTB family of transcriptional regulators, is one of four known genes—the other three being DNMT3B, CDCA7 and HELLS—that are mutated in immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome, a genetic disorder characterized by DNA hypomethylation and antibody deficiency. The molecular mechanisms by which ZBTB24 regulates gene expression and the biological functions of ZBTB24 are poorly understood. Here, we identified a 12-bp consensus sequence [CT(G/T)CCAGGACCT] occupied by ZBTB24 in the mouse genome. The sequence is present at multiple loci, including the Cdca7 promoter region, and ZBTB24 binding is mostly associated with gene activation. Crystallography and DNA-binding data revealed that the last four of the eight zinc fingers (ZFs) (i.e. ZF5-8) in ZBTB24 confer specificity of DNA binding. Two ICF missense mutations have been identified in the ZBTB24 ZF domain, which alter zinc-binding cysteine residues. We demonstrated that the corresponding C382Y and C407G mutations in mouse ZBTB24 abolish specific DNA binding and fail to induce Cdca7 expression. Our analyses indicate and suggest a structural basis for the sequence specific recognition by a transcription factor centrally important for the pathogenesis of ICF syndrome.

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Section: Resultsmentioning

confidence: 83%

Structural basis of specific DNA binding by the transcription factor ZBTB24

Ren

Hardikar

Horton

et al. 2019

Nucleic Acids Research

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“…The KRAB domain typically recruits the co-repressor KRAB-associated protein 1 (KAP1, also known as TRIM28, Tif1β), which serves as a scaffold protein for the further recruitment of co-repressors 5 . The C2H2 zinc finger domains determine a KZFP’s DNA-binding specificity, with each zinc finger typically, but not always 6 , recognizing three DNA bases 7 . The amino acids in positions 1, 2, 3, and 6 in the alpha helical region of each zinc finger directly interact with the DNA, thus acting as the most critical binding specificity determinants 8,9 , referred to as fingerprint 10 .…”

Section: Introductionmentioning

confidence: 99%

ZFP30 promotes adipogenesis through the KAP1-mediated activation of a retrotransposon-derived Pparg2 enhancer

et al. 2019

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Krüppel-associated box zinc finger proteins (KZFPs) constitute the largest family of mammalian transcription factors, but most remain completely uncharacterized. While initially proposed to primarily repress transposable elements, recent reports have revealed that KFZPs contribute to a wide variety of other biological processes. Using murine and human in vitro and in vivo models, we demonstrate here that one poorly studied KZFP, ZFP30, promotes adipogenesis by directly targeting and activating a retrotransposon-derived Pparg2 enhancer. Through mechanistic studies, we further show that ZFP30 recruits the co-regulator KRAB-associated protein 1 (KAP1), which, surprisingly, acts as a ZFP30 co-activator in this adipogenic context. Our findings provide an understanding of both adipogenic and KZFP-KAP1 complex-mediated gene regulation, showing that the KZFP-KAP1 axis can also function in a non-repressive manner.

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“…In order to understand how ZNF649 evolved to repress these elements, we synthesized 10 ZNF649 mutants (one for each ZNF domain) with each mutant designed to ablate the binding activity of a single finger. Canonically each ZNF within a KNZF recognizes three nucleotides of double stranded DNA via four specific DNA contact residues, typically (though not always) amino acids –1,2,3 and 6 relative to the ZNF helix 13,14 (Extended Data Fig 2); therefore, we mutated all four canonical DNA contact residues to alanine in each construct and tested each mutant’s ability to repress the L1PA4 luciferase reporter. Mutations to fingers 2,5,6,7 and 8 led to a loss of repression, indicating their importance in L1PA recognition.…”

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confidence: 99%

KRAB Zinc Finger Proteins coordinate across evolutionary time scales to battle retroelements

Fernandes

Haeussler

Armstrong

et al. 2018

Preprint

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23 24 2 KRAB Zinc Finger Proteins (KZNFs) are the largest and fastest evolving family of 25 human transcription factors 1,2 . The evolution of this protein family is closely 26 linked to the tempo of retrotransposable element (RTE) invasions, with specific 27 KZNF family members demonstrated to transcriptionally repress specific families 28 of RTEs 3,4 . The competing selective pressures between RTEs and the KZNFs 29 results in evolutionary arms races whereby KZNFs evolve to recognize RTEs, 30 while RTEs evolve to escape KZNF recognition 5 . Evolutionary analyses of the 31 primate-specific RTE family L1PA and two of its KZNF binders, ZNF93 and 32 ZNF649, reveal specific nucleotide and amino changes consistent with an arms 33 race scenario. Our results suggest a model whereby ZNF649 and ZNF93 worked 34 together to target independent motifs within the L1PA RTE lineage. L1PA 35 elements eventually escaped the concerted action of this KZNF "team" over ~30 36 million years through two distinct mechanisms: a slow accumulation of point 37 mutations in the ZNF649 binding site and a rapid, massive deletion of the entire 38 ZNF93 binding site. 39 40KZNFs repress RTEs by recruiting the co-factor Kap1 (Trim28) which then recruits a 41 variety of repressive factors that establish heterochromatin 1,6 . We reasoned that KZNFs 42 expressed highly in the pluripotent stem cell (PSC) state were likely to be involved in arms 43 race scenarios as the pluripotent state is a high stakes evolutionary battleground since 44 RTEs that successfully retrotranspose in this state are inherited by all daughter cells 45 including the germ line 7 . We further narrowed our investigation to the L1PA RTE lineage, 46 which contains the only active, autonomous RTE family (L1HS elements) in humans, and is therefore likely to experience high evolutionary pressure for repression 8 . Recent ChIP-48 SEQ studies have revealed many KZNFs that bind L1PA families (Extended Data Fig 1), 49 although these studies were performed in an artificial overexpression context in 293T 50 cells 4,9 . In order to analyze which of these binders might be important for repression in 51 the PSC context, we mapped KZNF ChIP-SEQ data to consensus repeat elements via 52 the UCSC Repeat Browser (MH, in preparation), and then correlated Repeat Browser 53 "meta-peaks" with Kap1 ChIP-SEQ "meta-peaks" from PSCs ( Fig 1A). This analysis 54 identified two KZNFs, ZNF649 and ZNF93 which are highly expressed in the PSC state 55 (Extended Data Fig 1), as responsible for the majority of Kap1 recruit on L1PA elements 56 in the human PSC context. We previously identified ZNF93 as an important repressor of 57 L1PA elements in hPSCs, and traced its binding site to a 129-bp region that was deleted 58 in the youngest (L1PA2, L1HS) L1PA families 5 . Interestingly, ZNF649 recognition of L1PA 59 elements is strongest on L1PA6-L1PA4 elements, appears to weaken in younger 60 elements (L1PA3-L1PA2), and is unable to bind L1HS elements ( Fig 1A). Additionally, 61 the correlation between Kap1 binding...

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DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins

Cited by 54 publications

References 71 publications

Structural basis of specific DNA binding by the transcription factor ZBTB24

Structural basis of specific DNA binding by the transcription factor ZBTB24

ZFP30 promotes adipogenesis through the KAP1-mediated activation of a retrotransposon-derived Pparg2 enhancer

KRAB Zinc Finger Proteins coordinate across evolutionary time scales to battle retroelements

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