DNA selection by the master transcription factor PU.1

Terrell, James R.; Taylor, Samuel J.; Schneider, Amelia L.; Lu, Yue; Vernon, Tyler; Xhani, Suela; Gumpper, Ryan H.; Luo, Ming; Wilson, W. David; Steidl, Ulrich; Poon, Gregory M.K.

doi:10.1016/j.celrep.2023.112671

Cited by 6 publications

(8 citation statements)

References 71 publications

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“…The master transcriptional regulator PU.1, also known as Spi-1, exhibits a distinct preference for purines at the Q226 position, which is integral to its DNA binding specificity. This preference is pivotal in understanding the pathogenesis of the Q226E mutation observed in Waldenström macroglobulinemia, a finding that aligns with the high-resolution PU.1 structures presented by Terrell et al [12]. Furthermore, our study suggests that K237 plays an essential role in SPI1-DNA binding, as its DNA-binding capability is compromised in the E226 mutation context.…”

Section: Spi1 and Dna Bindingsupporting

confidence: 88%

“…Our findings, supported by high-resolution structural data from Terrell et al [12], emphasize the significance of evolutionary innovations like Q226 in PU.1 and their role in preserving the structural and functional integrity of transcription factors. The comprehensive understanding of SPI1-DNA interactions, especially in the context of pathogenic mutations, forms a basis for further research into the molecular mechanisms driving transcriptional dysregulation in diseases like Waldenström macroglobulinemia.…”

Section: Spi1 and Dna Bindingsupporting

confidence: 82%

“…Building upon these datasets, we further demonstrated the functional applications of ARIP using four additional examples. These included the analysis of the NMR structure of PDB 1MEK, the examination of protein-DNA interactions in 22 SPI1 complexes with DNA [12], the investigation of protein-ligand interactions in 2 CYP17A1 structures with bound ligands [11], and the identification of key residues during molecular dynamics simulations using 3 structures from MD simulations of PDB 5ULA [10]. These examples showcased the versatility of ARIP in various biological contexts, highlighting its utility in understanding protein structure and function.…”

Section: Datasetmentioning

confidence: 99%

“…The software has been used to analyze around 1151 protein structures obtained through Nuclear Magnetic Resonance (NMR) technology, aiding in the capture of dynamic residue contacts. It was specifically employed for key residue capture in NMR PDB files (e.g., 1MEK) [9], molecular dynamic simulation capture of the BRD4 protein (four states) [10], ligand binding capture of CYP17A1 structures with drugs [11], and DNA binding interactions of the SPI1 protein-DNA complex structures [12]. In summary, ARIP is a comprehensive and user-friendly software tool that supports the analysis of nucleic acids and other molecules stored in PDB format.…”

Section: Introductionmentioning

confidence: 99%

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ARIP: A Tool for Precise Interatomic Contact Area and Volume Calculation in Proteins

Ma,

Li,

Tang

et al. 2024

IJMS

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The interplay patterns of amino acid residues are pivotal in determining the tertiary structure and flexibility of proteins, which in turn are intricately linked to their functionality and interactions with other molecules. Here, we introduce ARIP, a novel tool designed to identify contact residues within proteins. ARIP employs a modified version of the dr_sasa algorithm and an atomic overlap weighted algorithm to directly calculate the contact area and volume between atoms based on their van der Waals radius. It also allows for the selection of solvent radii, recognizing that not every atom in proteins can interact with water molecules. The solvent parameters were derived from the analysis of approximately 5000 protein and nucleic acid structures with water molecules determined using X-ray crystallography. One advantage of the modified algorithm is its capability to analyze multiple models within a single PDB file, making it suitable for molecular dynamic capture. The contact volume is symmetrically distributed between the interacting atoms, providing more informative results than contact area for the analysis of intra- and intermolecular interactions and the development of scoring functions. Furthermore, ARIP has been applied to four distinct cases: capturing key residue–residue contacts in NMR structures of P4HB, protein–drug binding of CYP17A1, protein–DNA binding of SPI1, and molecular dynamic simulations of BRD4.

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Section: Spi1 and Dna Bindingsupporting

confidence: 88%

Section: Spi1 and Dna Bindingsupporting

confidence: 82%

Section: Datasetmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ARIP: A Tool for Precise Interatomic Contact Area and Volume Calculation in Proteins

Ma,

Li,

Tang

et al. 2024

IJMS

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“…To test these possibilities, we looked at the DNA methylation dynamics associated with altered Cdx2 binding between developmental and adult timepoints (Figure 1A). Pioneer TFs such as NRF1 and PU.1 that preferentially bind methylated DNA can recruit demethylases like Tet2 to demethylate their binding site and surrounding CpGs, which creates an opportunity for other DNA methylation sensitive TFs to bind at the locus 6,32,33 . Therefore, we considered the temporal changes in DNA methylation surrounding the Cdx2 binding peaks as well as at the CpG within the CpG-containing motif (4 th base position, Figure S2A).…”

Section: Resultsmentioning

confidence: 99%

DNA methylation-dependent and -independent binding of CDX2 directs activation of distinct developmental and homeostatic genes

Lorzadeh,

Ye,

Sharma

et al. 2024

Preprint

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Precise spatiotemporal and cell type-specific gene expression is essential for proper tissue development and function. Transcription factors (TFs) guide this process by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of TFs. However, how TFs navigate various chromatin features and selectively bind a small portion of the millions of possible genomic target loci is still not well understood. Here we show that Cdx2 - a pioneer TF that binds distinct targets in developing versus adult intestinal epithelial cells - has a preferential affinity for a non-canonical CpG-containing motif in vivo. A higher frequency of this motif at embryonic and fetal Cdx2 target loci and the specifically methylated state of the CpG during development allows selective Cdx2 binding and activation of developmental enhancers and linked genes. Conversely, demethylation at these enhancers prohibits ectopic Cdx2 binding in adult cells, where Cdx2 binds its canonical motif without a CpG. This differential Cdx2 binding allows for corecruitment of Ctcf and Hnf4, facilitating the establishment of intestinal superenhancers during development and enhancers mediating adult homeostatic functions, respectively. Induced gain of DNA methylation in the adult mouse epithelium or cultured cells causes ectopic recruitment of Cdx2 to the developmental target loci and facilitates cobinding of the partner TFs. Together, our results demonstrate that the differential CpG motif requirements for Cdx2 binding to developmental versus adult target sites allow it to navigate different DNA methylation profiles and activate cell type-specific genes at appropriate times.

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The Diverse Roles of ETV6 Alterations in B-Lymphoblastic Leukemia and Other Hematopoietic Cancers

Monovich,

Gurumurthy,

Ryan

2024

Transcription Factors in Blood Cell Development

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DNA selection by the master transcription factor PU.1

Cited by 6 publications

References 71 publications

ARIP: A Tool for Precise Interatomic Contact Area and Volume Calculation in Proteins

ARIP: A Tool for Precise Interatomic Contact Area and Volume Calculation in Proteins

DNA methylation-dependent and -independent binding of CDX2 directs activation of distinct developmental and homeostatic genes

The Diverse Roles of ETV6 Alterations in B-Lymphoblastic Leukemia and Other Hematopoietic Cancers

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