MAGGIE: leveraging genetic variation to identify DNA sequence motifs mediating transcription factor binding and function

Shen, Zeyang; Hoeksema, Marten A.; Ouyang, Zhengyu; Benner, Christopher; Glass, Christopher K.

doi:10.1101/2020.01.30.925917

Cited by 8 publications

(20 citation statements)

References 49 publications

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“…We applied this tool to strain-differential IL-4-responsive enhancers and transcription factor binding sites. Strain-differential IL-4 responsive enhancers were defined as previously described for KLA-responsive enhancers (Shen et al, 2020). In brief, from every pairwise comparison across the five strains, enhancers identified as “IL-4 activated” or “IL-4 repressed” only in one of the compared strains were called strain-differential and were pooled together.…”

Section: Star Methodsmentioning

confidence: 99%

“…As a genetic approach to identify functional transcriptional factor binding motifs, we assessed the quantitative impact of the genetic variation provided by the five different strains of mice on the IL-4 response of enhancers using the motif mutation analysis tool MAGGIE (Shen et al, 2020).…”

Section: Motif Mutation Analysis Identifies Motifs That Are Functionamentioning

confidence: 99%

“…Motif mutation analysis. To integrate the genetic variation across mouse strains into motif analysis, we used MAGGIE, which is able to identify functional motifs out of the currently known motifs by testing for the association between motif mutations and the changes in specific epigenomic features (Shen et al, 2020). The known motifs are obtained from the JASPAR database (Fornes et al, 2020).…”

Section: Motif Analysismentioning

confidence: 99%

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Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

Hoeksema

Shen

Holtman

et al. 2020

Preprint

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Mechanisms by which non-coding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million SNPs and InDels provided by five inbred strains of mice on the responses of macrophages to interleukin 4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Remarkably, of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage determining and signal-dependent transcription factors driving late enhancer activation. These studies further revealed mechanisms by which non-coding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.

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Section: Star Methodsmentioning

confidence: 99%

Section: Motif Mutation Analysis Identifies Motifs That Are Functionamentioning

confidence: 99%

Section: Motif Analysismentioning

confidence: 99%

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Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

Hoeksema

Shen

Holtman

et al. 2020

Preprint

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“…To fully evaluate whether the strain-specific binding peaks are due to the changes in the sequence-specific affinity to which CodY is bound, we first identified a 20-bp motif based on a merged set of CodY binding peaks from the strains using MEME (20) (Supplementary figure 6). We then utilized the computational method MAGGIE to measure differences in the DNA sequence in paired binding sites in the two strains (21).…”

Section: Strain-specific Binding Intensity Is Associated With Dna Seqmentioning

confidence: 99%

“…To gain insights into the CodY motifs from TCH1516 and LAC strains, MAGGIE was used for motif mutation analysis (21). For CodY, given a pair of CodY binding sequences of the same target gene from TCH1516 and LAC strains, the peak sequence with a higher binding intensity was considered as a positive sequence; the other one with a lower binding intensity was considered as a negative sequence.…”

Section: Motif Mutation Analysismentioning

confidence: 99%

Elucidating the CodY regulon inStaphylococcus aureusUSA300 substrains

Gao

Poudel

Seif

et al. 2021

Preprint

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CodY is a conserved broad acting transcription factor that regulates the expression of genes related to amino acid metabolism and virulence in methicillin-resistant Staphylococcus aureus (MRSA). CodY target genes have been studied by using in vitro DNA affinity purification and deep sequencing (IDAP-Seq). Here we performed the first in vivo determination of CodY target genes using a novel CodY monoclonal antibody in established ChIP-exo protocols. Our results showed, 1) the same 135 CodY promoter binding sites regulating 165 target genes identified in two closely related virulent S. aureus USA300 TCH1516 and LAC strains; 2) The differential binding intensity for the same target genes under the same conditions was due to sequence differences in the same CodY binding site in the two strains; 3) Based on transcriptomic data, a CodY regulon comprising 72 target genes that are differentially regulated relative to a CodY deletion strain, representing genes that are mainly involved in amino acid transport and metabolism, inorganic ion transport and metabolism, transcription and translation, and virulence; and 4) CodY systematically regulated central metabolic flux to generate branched-chain amino acids (BCAAs) by mapping the CodY regulon onto a genome-scale metabolic model of S. aureus. Our study performed the first system-level analysis of CodY in two closely related USA300 TCH1516 and LAC strains giving new insights into the similarities and differences of CodY regulatory roles between the closely related strains.ImportanceWith the increasing availability of whole genome sequences for many strains within the same pathogenic species, a comparative analysis of key regulators is needed to understand how the different strains uniquely coordinate metabolism and expression of virulence. To successfully infect the human host, Staphylococcus aureus USA300 relies on the transcription factor CodY to reorganize metabolism and express virulence factors. While CodY is a known key transcription factor, its target genes are not characterized on a genome-wide basis. We performed a comparative analysis to describe the transcriptional regulation of CodY between two dominant USA300 strains. This study motivates the characterization of common pathogenic strains and an evaluation of the possibility of developing specialized treatments for major strains circulating in the population.

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Sexual Dimorphism in Differentiating Osteoclast Precursors Demonstrates Enhanced Inflammatory Pathway Activation in Female Cells

Mun

Jastrzebski

Kalinowski

et al. 2020

Journal of Bone and Mineral Research

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Sexual dimorphism of the skeleton is well documented. At maturity, the male skeleton is typically larger and has a higher bone density than the female skeleton. However, the underlying mechanisms for these differences are not completely understood. In this study, we examined sexual dimorphism in the formation of osteoclasts between cells from female and male mice. We found that the number of osteoclasts in bones was greater in females. Similarly, in vitro osteoclast differentiation was accelerated in female osteoclast precursor (OCP) cells. To further characterize sex differences between female and male osteoclasts, we performed gene expression profiling of cultured, highly purified, murine bone marrow OCPs that had been treated for 3 days with macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL). We found that 125 genes were differentially regulated in a sex‐dependent manner. In addition to genes that are contained on sex chromosomes, transcriptional sexual dimorphism was found to be mediated by genes involved in innate immune and inflammatory response pathways. Furthermore, the NF‐κB‐NFATc1 axis was activated earlier in female differentiating OCPs, which partially explains the differences in transcriptomic sexual dimorphism in these cells. Collectively, these findings identify multigenic sex‐dependent intrinsic difference in differentiating OCPs, which results from an altered response to osteoclastogenic stimulation. In humans, these differences could contribute to the lower peak bone mass and increased risk of osteoporosis that females demonstrate relative to males. © 2021 American Society for Bone and Mineral Research (ASBMR).

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MAGGIE: leveraging genetic variation to identify DNA sequence motifs mediating transcription factor binding and function

Cited by 8 publications

References 49 publications

Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

Elucidating the CodY regulon inStaphylococcus aureusUSA300 substrains

Sexual Dimorphism in Differentiating Osteoclast Precursors Demonstrates Enhanced Inflammatory Pathway Activation in Female Cells

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