Can the Concentration of a Transcription Factor Affect Gene Expression?

Koşar, Zafer; Erbaş, Aykut

doi:10.3389/frsfm.2022.914494

Cited by 12 publications

(7 citation statements)

References 58 publications

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“…We compared TFBS enrichment to the corresponding TF expression, finding several TFs to be both differentially expressed and enriched in chromatin accessible regions ( Extended Data Fig.3d ). However, we did not find statistically significant correlation (r > 0.5, Pearson correlation) between TF expression and motif enrichment, possibly as TF concentration is not the sole determinants of DNA binding 89 . However, a small number of TFs which had enriched TFBS in a cluster-specific manner had high expression in the corresponding clusters.…”

Section: Resultscontrasting

confidence: 87%

“…3d). However, we did not find statistically significant correlation (r > 0.5, Pearson correlation) between TF expression and motif enrichment, possibly as TF concentration is not the sole determinants of DNA binding 89 . However, a small number of TFs which had enriched TFBS in a cluster-specific manner had high expression in the corresponding clusters.…”

Section: Motif Enrichment Analyses Identify Cell-type Specific Regula...contrasting

confidence: 87%

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Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

Nguyen

Chan

Cintron

et al. 2022

Preprint

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Over 500 noncoding genomic loci are associated with obesity. The majority of these loci reside near genes that are expressed in the hypothalamus in specific neuronal subpopulations that regulate food intake, hindering the ability to identify and functionally characterize them. Here, we carried out integrative single-cell analysis (RNA/ATAC-seq) on both mouse and human male and female hypothalamus to characterize genes and regulatory elements in specific cell subpopulations. Utilizing both transcriptome and regulome data, we identify over 30 different neuronal and non-neuronal cell subpopulations and a shared core of transcription factors that regulate cell cluster-specific genes between mice and humans. We characterize several sex-specific differentially expressed genes and the regulatory elements that control them in specific cell subpopulations. Overlapping cell-specific scATAC peaks with obesity-associated GWAS variants, identifies potential obesity-associated regulatory elements. Using reporter assays and CRISPR editing, we show that many of these sequences, including the top obesity-associated loci (FTO and MC4R), are functional enhancers whose activity is altered due to the obesity-associated variant and regulate known obesity genes. Combined, our work provides a catalog of genes and regulatory elements in hypothalamus cell subpopulations and uses obesity to showcase how integrative single-cell sequencing can identify functional variants associated with hypothalamus-related phenotypes.

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Section: Resultscontrasting

confidence: 87%

Section: Motif Enrichment Analyses Identify Cell-type Specific Regula...contrasting

confidence: 87%

Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

Nguyen

Chan

Cintron

et al. 2022

Preprint

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“…The Caco2 cells display a wider distribution of the CD133 expression level than the HT-29 and HUH7 cells ( Figure 1 ), allowing the detection of even minor changes in the CD133 expression. The downregulation of TRIM28 by shRNA did not affect CD133 expression, suggesting that even a decreased amount of TRIM28 could maintain the CD133 level, as was shown for some other transcription factors that could activate transcription at very low concentrations [ 56 , 57 ]. The difference in the effects of large and small amounts of certain transcription factors on target genes expression was also demonstrated in vivo.…”

Section: Discussionmentioning

confidence: 94%

TRIM28 Is a Novel Regulator of CD133 Expression Associated with Cancer Stem Cell Phenotype

Potashnikova

Gisina

et al. 2022

IJMS

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CD133 is an extensively studied marker of the most malignant tumor cell population, designated as cancer stem cells (CSCs). However, the function of this glycoprotein and its involvement in cell regulatory cascades are still poorly understood. Here we show a positive correlation between the level of CD133 plasma membrane expression and the proliferative activity of cells of the Caco-2, HT-29, and HUH7 cancer cell lines. Despite a substantial difference in the proliferative activities of cell populations with different levels of CD133 expression, transcriptomic and proteomic profiling revealed only minor distinctions between them. Nonetheless, a further in silico assessment of the differentially expressed transcripts and proteins revealed 16 proteins that could be involved in the regulation of CD133 expression; these were assigned ranks reflecting the apparent extent of their involvement. Among them, the TRIM28 transcription factor had the highest rank. The prominent role of TRIM28 in CD133 expression modulation was confirmed experimentally in the Caco2 cell line clones: the knockout, though not the knockdown, of the TRIM28 gene downregulated CD133. These results for the first time highlight an important role of the TRIM28 transcription factor in the regulation of CD133-associated cancer cell heterogeneity.

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“…It is therefore noteworthy that we observed a consistent species-wide trend of nonadditive expression leading to the relative gene-expression level in F1 hybrids being more similar to the low-expression parents. With the proviso that we cannot rule out that the absolute transcript abundance of these genes were in fact increasing, our measurements do indicate a relative decrease in cellular transcript concentration, which could have consequences for molecular interactions (Gao et al 2021;Koşar and Erbaş 2022). The abundance of up-stream rare alleles in these non-additively expressed genes further suggests that the change of expression had a genetic basis, as opposed to being merely a consequence of a common phenotype.…”

Section: Non-additivity In Arabidopsismentioning

confidence: 73%

Pervasive Under-Dominance in Gene Expression Underlying Emergent Growth Trajectories inArabidopsis thalianaHybrids

Yuan

Beitel

Srikant

et al. 2022

Preprint

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Heterosis, the generally superior performance in hybrids compared to their inbred parents, is one of the most enigmatic biological phenomena. Many different explanations have been put forward for heterosis, which begs the question whether common principles underpinning it do exist at all. We performed a systematic transcriptomic study in Arabidopsis thaliana involving 141 random crosses, to search for the general principles, if any, that heterotic hybrids share. Consistent additive expression in F1 hybrids was observed for only about 300 genes enriched for roles in stress response and cell death. Regulatory rare-allele burden affects the expression level of these genes but does not correlate with heterosis. Non-additive gene expression in F1 hybrids is much more common, with the vast majority of genes (over 90%) being expressed below parental average. These include genes that are quantitatively correlated with biomass accumulation in both parents and F1 hybrids, as well as genes strongly associated with heterosis. Unlike in the additive genes, regulatory rare allele burden in this non-additive gene set is strongly correlated with growth heterosis, even though it does not covary with the expression level of these genes. Together, our study suggests that while additive complementation is an intrinsic property of F1 hybrids, the major driver of growth in hybrids derives from the quantitative nature of non-additive gene expression, especially under-dominance and thus lower expression in hybrids than predicted from the parents.

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Can the Concentration of a Transcription Factor Affect Gene Expression?

Cited by 12 publications

References 58 publications

Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

TRIM28 Is a Novel Regulator of CD133 Expression Associated with Cancer Stem Cell Phenotype

Pervasive Under-Dominance in Gene Expression Underlying Emergent Growth Trajectories inArabidopsis thalianaHybrids

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