Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming

Soufi, Abdenour; García, Meilín Fernández; Jaroszewicz, Artur; Osman, Nebiyu; Pellegrini, Matteo; Zaret, Kenneth S.

doi:10.1016/j.cell.2015.03.017

Cited by 659 publications

(927 citation statements)

References 84 publications

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“…However, recent studies with KLF4, which is highly related to KLF1 (Bieker, 2001), suggest that zinc fingers 2 and 3 play a necessary and dominant role in targeting its recognition site within nucleosomes (Soufi et al, 2015). In the present case, the amino acid change is located within zinc finger 2 and thus could enable Nan-KLF1 to play a role as a pioneer factor at ectopic sites in spite of their lower accessibility in the red cell.…”

Section: Discussionmentioning

confidence: 62%

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Planutis

Xue

Trainor³

et al. 2017

Development

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Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/ KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.

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Section: Discussionmentioning

confidence: 62%

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Planutis

Xue

Trainor³

et al. 2017

Development

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“…Sequence-dependent recognition of DNA wrapped on the nucleosome core may play a functional role for pioneer transcription factors such as FoxA, Oct4, Sox2, and Klf4 (28,29). Unfortunately, there are no structures of pioneer factors bound to a nucleosome, and the existing structures of nucleosome corebinding proteins bound to a NCP are nonspecific complexes that make little contact with NCP DNA (20,22,30).…”

Section: Discussionmentioning

confidence: 99%

X-ray structure of the MMTV-A nucleosome core

Frouws

Duda

Richmond

2016

Proc. Natl. Acad. Sci. U.S.A.

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The conformation of DNA bound in nucleosomes depends on the DNA sequence. Questions such as how nucleosomes are positioned and how they potentially bind sequence-dependent nuclear factors require near-atomic resolution structures of the nucleosome core containing different DNA sequences; despite this, only the DNA for two similar α-satellite sequences and a sequence (601) selected in vitro have been visualized bound in the nucleosome core. Here we report the 2.6-Å resolution X-ray structure of a nucleosome core particle containing the DNA sequence of nucleosome A of the 3′-LTR of the mouse mammary tumor virus (147 bp MMTV-A). To our knowledge, this is the first nucleosome core particle structure containing a promoter sequence and crystallized from Mg 2+ ions. It reveals sequence-dependent DNA conformations not seen previously, including kinking into the DNA major groove.chromatin | nucleosome | DNA | X-ray structure | MMTV D NA in eukaryotic cells is wrapped repeatedly in nucleosomes to form chromatin, the substrate engaged by the nuclear machinery to carry out repair, replication, recombination, and transcription of genomes. Nucleosome mapping in situ combined with biochemical studies has revealed that nucleosome positions determine access to DNA regulatory sequences essential to these processes (1, 2). Nucleosome position is determined chiefly by DNA sequence and ATP-dependent chromatin remodeling factors (3-5). The nucleosome includes a linker DNA of variable length and a nucleosome core containing a histone octamer and 147 bp of DNA (6). Many high-resolution structures of nucleosome cores with differing DNA sequences are required to see how the details of DNA conformation could affect nucleosome positioning and dynamics, as well as nuclear factor binding. The DNA studied would most interestingly represent natural sequences of transcription promoters and enhancer elements.Our knowledge of sequence-dependent structure of DNA bound in the nucleosome core relative to the amount of DNA bound in genomes is extremely limited. A resolution of at least 2.6 Å is necessary to evaluate differences in DNA conformations and assess solvent interactions adequately. To date, this highly reliable "library" of DNA structural information pertinent to the nucleosome core consists primarily of two similar sequences of half α-satellite repeats and half the artificially "evolved" sequence 601 (7-10). Further investigations have been limited to substitution of short sequence elements in one of the α-satellite sequences (11, 12). These high-resolution structures have hinged on using palindromic sequences to avoid twofold averaging imposed by crystal packing. The lack of twofold symmetry in the full 601 sequence, for example, resulted in superposition of the electron density of the two different half-sequences (9).We describe here the X-ray structure of a nucleosome core particle (NCP) containing a DNA sequence from mouse mammary tumor virus (MMTV) determined at 2.6 Å resolution. To our knowledge, this is the first NCP structure conta...

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“…A few transcription factors are known to possess the ability to bind cognate sites on nucleosomes and evoke subsequent remodeling of chromatin (58). Such "pioneer" factors facilitate binding by other transcription factors and are usually necessary for the maintenance of cell identity.…”

Section: Discussionmentioning

confidence: 99%

Synthetic genome readers target clustered binding sites across diverse chromatin states

Erwin

Grieshop

Bhimsaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Targeting the genome with sequence-specific DNA-binding molecules is a major goal at the interface of chemistry, biology, and precision medicine. Polyamides, composed of N-methylpyrrole and N-methylimidazole monomers, are a class of synthetic molecules that can be rationally designed to “read” specific DNA sequences. However, the impact of different chromatin states on polyamide binding in live cells remains an unresolved question that impedes their deployment in vivo. Here, we use cross-linking of small molecules to isolate chromatin coupled to sequencing to map the binding of two bioactive and structurally distinct polyamides to genomes directly within live H1 human embryonic stem cells. This genome-wide view from live cells reveals that polyamide-based synthetic genome readers bind cognate sites that span a range of binding affinities. Polyamides can access cognate sites within repressive heterochromatin. The occupancy patterns suggest that polyamides could be harnessed to target loci within regions of the genome that are inaccessible to other DNA-targeting molecules.

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Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming

Cited by 659 publications

References 84 publications

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

X-ray structure of the MMTV-A nucleosome core

Synthetic genome readers target clustered binding sites across diverse chromatin states

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