Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-binding Domains of the ETS Family Transcription Factors Ets-1 and PU.1

Wang, Shuo; Linde, Miles H.; Munde, Manoj; Carvalho, Victor D.; Wilson, W. David; Poon, Gregory M.K.

doi:10.1074/jbc.m114.575340

Cited by 28 publications

(54 citation statements)

References 69 publications

(92 reference statements)

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“…Exogenous PU.1 expression in fibroblasts also induces accessible chromatin at de novo PU.1-binding sites in the inducible enhancers. PU.1 uses hydration to recognize target DNA and forms a long-lived complex relative to the other Ets factors, which use electrostatic interactions (Wang et al 2014). We speculate that the hydration-based recognition imparts the necessary adaptability for PU.1 to bind nucleosomal DNA.…”

Section: Pioneer Factors In Cell Programming During Developmentmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in ''closed'' chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as ''pioneer factors'' to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

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Section: Pioneer Factors In Cell Programming During Developmentmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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“…56 Using physiologically compatible osmolytes to modulate the osmotic environment (water activity), the data indeed showed that high-affinity DNA binding by PU.1 was osmotic sensitive while binding by Ets-1 was not (Table 1). Moreover, the osmotic sensitivity of PU.1, wherein affinity was reduced by osmotic pressure, was dependent on the DNA sequence context, inferring a direct role of hydration in the specificity mechanism of PU.1.…”

Section: Role Of Molecular Hydration In Dna Recognition By Ets Proteinsmentioning

confidence: 93%

“…ETS paralogs are formally categorized into classes I-IV 27 by color in order from black, blue, orange, to yellow. (C) Differential sensitivity to osmotic pressure in site-specific binding by the ETS domains of PU.1 and Ets-1 as reported by Wang et al 56 The measured in vitro affinity is expressed as the logarithm of the dissociation constant (K D ). High-(solid symbols) and low-affinity DNA (open) refer to defined cognate (not nonspecific) sequences harboring the 5 0 -GGAA-3 0 consensus.…”

Section: Differential Tolerance To Cpg Methylationmentioning

confidence: 99%

“…First, they are archetypal representatives of the most phylogenetically most distant classes of ETS proteins, 49 so heterogeneity in their molecular phenotype should directly reflect the selection pressures in their evolutionary paths, even if the biologic basis of these pressures are not necessarily known. Second, these two ETS paralogs bind optimal DNA targets with indistinguishably high affinity, 56 so that heterogeneity between the two homologs that contribute to their DNA binding affinity and specificity would be biologically relevant.…”

Section: A Deeper Look Into Ets/dna Recognitionmentioning

confidence: 99%

“…The osmotic insensitivity of Ets-1 is not modified by the presence of auto-inhibition. 56 sensitivity to CpG methylation among ETS transcription factors. They confirmed the strong inhibition of Ets-1 (and by extension, other class I ETS members) by full CpG methylation and provided a basis for the genomic-wide observation PU.1 to autonomously engage methylated DNA in vivo.…”

Section: Differential Tolerance To Cpg Methylationmentioning

confidence: 99%

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Signatures of DNA target selectivity by ETS transcription factors

Poon

Kim

2017

Transcription

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The ETS family of transcription factors is a functionally heterogeneous group of gene regulators that share a structurally conserved, eponymous DNA-binding domain. DNA target specificity derives from combinatorial interactions with other proteins as well as intrinsic heterogeneity among ETS domains. Emerging evidence suggests molecular hydration as a fundamental feature that defines the intrinsic heterogeneity in DNA target selection and susceptibility to epigenetic DNA modification. This perspective invokes novel hypotheses in the regulation of ETS proteins in physiologic osmotic stress, their pioneering potential in heterochromatin, and the effects of passive and pharmacologic DNA demethylation on ETS regulation.

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Resolution of Mixed Site DNA Complexes with Dimer‐Forming Minor‐Groove Binders by Using Electrospray Ionization Mass Spectrometry: Compound Structure and DNA Sequence Effects

Laughlin

Wang

Kumar

et al. 2015

Chemistry A European J

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Small molecule targeting of the DNA minor groove is a promising approach to modulate genomic processes necessary for normal cellular function. For instance, dicationic diamindines, a well-known class of minor groove binding compounds, have been shown to inhibit interactions of transcription factors binding to genomic DNA. The applications of these compounds could be significantly expanded if we understand sequence-specific recognition of DNA better and could use the information to design more sequence-specific compounds. Aside from polyamides, minor groove binders typically recognize DNA at A-tract or alternating AT base pair sites. Targeting sites with GC base pairs, referred to here as mixed base pair sequences, is much more difficult than those rich in AT base pairs. Compound 1 is the first dicationic diamidine reported to recognize a mixed base pair site. It binds in the minor groove of ATGA sequences as a dimer with positive cooperativity. Due to the well-characterized behavior of 1 with ATGA and AT rich sequences, it provides a paradigm for understanding the elements that are key for recognition of mixed sequence sites. Electrospray ionization mass spectrometry (ESI-MS) is a powerful method to screen DNA complexes formed by analogs of 1 for specific recognition. We also report a novel approach to determine patterns of recognition by 1 for cognate ATGA and ATGA-mutant sequences. We found that functional group modifications and mutating the DNA target site significantly affect binding and stacking, respectively. Both compound conformation and DNA sequence directionality are crucial for recognition.

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Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-binding Domains of the ETS Family Transcription Factors Ets-1 and PU.1

Cited by 28 publications

References 69 publications

Pioneer transcription factors in cell reprogramming

Pioneer transcription factors in cell reprogramming

Signatures of DNA target selectivity by ETS transcription factors

Resolution of Mixed Site DNA Complexes with Dimer‐Forming Minor‐Groove Binders by Using Electrospray Ionization Mass Spectrometry: Compound Structure and DNA Sequence Effects

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