Neglected Functions of TFCP2/TFCP2L1/UBP1 Transcription Factors May Offer Valuable Insights into Their Mechanisms of Action

Taracha, Agnieszka; Kotarba, Grzegorz; Wilanowski, Tomasz

doi:10.3390/ijms19102852

Cited by 32 publications

(27 citation statements)

References 70 publications

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“…Genes with age-dependent decrease in expression (Type 2) These changes may reflect the injury associated with disease progression, and could be potential targets or biomarkers candidates. Only one gene showed decreased expression with age: UBP1, a protein coding gene whose product is a transcriptional activator [90]. While for mice this gene is expressed in astrocytes, the human orthologue is expressed in neurons (see Figure 5B).…”

Section: Age-dependent Degsmentioning

confidence: 99%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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Understanding Parkinson's disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD. 1/30 models provide a useful means to investigate PD-associated molecular changes, in particular those preceding nigro-striatal degeneration. The elucidation of such early changes can shed light into disease causation and drivers of disease progression, thus in turn pointing to novel targets for intervention as well as biomarkers [16,45].Whole transcriptome analysis enables to compare thousands of genes between two or more groups [9], and provides a valuable method for identifying coordinated changes in gene expression patterns that are not captured by single-gene or protein measurement approaches [59]. Despite of these advantages, only a limited amount of studies have used transcriptomics on α-synuclein-based transgenic mouse models for PD [13, 67, 71-73, 94, 98]. Alpha-synuclein, a pre-synaptic protein believed to be a moderator of the synaptic vesicle cycle, is a major component of Lewy bodies [87]. In addition, mutations or multiplications in its genes leads to familiar forms of PD [26,46]. Transcriptomics studies on α-synuclein-based transgenic mouse models for PD have only looked at differentially expressed genes (DEGs) in relation to pre-defined cellular pathways or gene sets from public annotation databases [13,67,[71][72][73]94]. Most of them used only one [71][72][73] or two age groups [13,67,94,98] of the mouse model for their analyses, and some of them were perform...

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Section: Age-dependent Degsmentioning

confidence: 99%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Furthermore, there was no overlap in the significant genes nominated among the four ethnicities. For example, we found significant evidence of a genetic association on chromosome 2q14.2 with weight and waist circumference in EAs; these two QTNs (rs139940998, rs144756634) are located in between GLI2 and TFCP2L1 , which is expressed in the kidneys [ 72 ] and may act as a transcriptional suppressor of UBP1-mediated transcription activation [ 73 ]. Moreover, rs139940998 was identified as being functional across multiple annotations (Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis of metabolic syndrome quantitative traits in the GENNID multiethnic family study

Wan

Goodman

Willems

et al. 2021

Diabetol Metab Syndr

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Background To identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups. Methods Data was collected from GENetics of Noninsulin dependent Diabetes Mellitus (GENNID), a multiethnic resource of Type 2 diabetic families and included 1520 subjects in 259 African-American, European-American, Japanese-Americans, and Mexican-American families. We focused on eight MetS traits: weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein, triglycerides, fasting glucose, and insulin. Using genotyped and imputed data from Illumina’s Multiethnic array, we conducted genome-wide association analyses with linear mixed models for all ethnicities, except for the smaller Japanese-American group, where we used additive genetic models with gene-dropping. Results Findings included ethnic-specific genetic associations and heterogeneity across ethnicities. Most significant associations were outside our candidate linkage regions and were coincident within a gene or intergenic region, with two exceptions in European-American families: (a) within previously identified linkage region on chromosome 2, two significant GLI2-TFCP2L1 associations with weight, and (b) one chromosome 11 variant near CADM1-LINC00900 with pleiotropic blood pressure effects. Conclusions This multiethnic family study found genetic heterogeneity and coincident associations (with one case of pleiotropy), highlighting the importance of including diverse populations in genetic research and illustrating the complex genetic architecture underlying MetS.

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“…This gene has recently been identified as the most predictive age-related gene across mammalian species and despite its conserved status, its contribution towards age-related functional decline has not be clarified[37]. The top two hypomethylated CpGs (both within introns) in the blood were proximal to UBP1 , a gene that is closely related to TFCP2 and is considered part of the Grainyhead family of transcription factors[46]. Although UBPI has been identified as involved in angiogenesis during growth and development and Alzheimer’s disease, its redundancy and homology with TFCP2 make its yet unidentified role in cancer regulation a likely possibility[46, 47].…”

Section: Discussionmentioning

confidence: 99%

“…The top two hypomethylated CpGs (both within introns) in the blood were proximal to UBP1 , a gene that is closely related to TFCP2 and is considered part of the Grainyhead family of transcription factors[46]. Although UBPI has been identified as involved in angiogenesis during growth and development and Alzheimer’s disease, its redundancy and homology with TFCP2 make its yet unidentified role in cancer regulation a likely possibility[46, 47]. For skin, the top proximate genes were associated with development and energy metabolism (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Multi-tissue methylation clocks for age estimation in the common bottlenose dolphin

Robeck

Fei

Haghani

et al. 2021

Preprint

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Accurate identification of individual ages within wild bottlenose dolphins (Tursiops truncatus) is critical for determining population health and the development of population management strategies. As such, we analyzed DNA methylation patterns by applying a custom methylation array (HorvathMammalMethyl40) to both blood (n = 140) and skin samples (n = 87) from known age or approximate age (0 to 57 years) bottlenose dolphins. We present three bottlenose dolphin specific age estimation clocks using combined blood and skin (48 CpGs, R = 0.93, median absolute error = 2.13 years), blood only (64 CpGs, R = 0.97, error= 1.46 years) and skin only (39 CpGs, R = 0.95, error= 2.53). Our sex estimator based on 71 CpGs predicts the sex of any odontocete species with 99.5% accuracy. We characterize individual cytosines that correlate with sex and age in dolphins. The presented epigenetic clocks are expected to be useful for conservation efforts and for studying anthropogenic events.

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Neglected Functions of TFCP2/TFCP2L1/UBP1 Transcription Factors May Offer Valuable Insights into Their Mechanisms of Action

Cited by 32 publications

References 70 publications

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Genome-wide association analysis of metabolic syndrome quantitative traits in the GENNID multiethnic family study

Multi-tissue methylation clocks for age estimation in the common bottlenose dolphin

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