Characterization of enhancers and the role of the transcription factor KLF7 in regulating corneal epithelial differentiation

Klein, Rachel Herndon; Hu, William; Kashgari, Ghaidaa; Lin, Ziguang; Nguyen, Tuyen; Doan, Michael; Andersen, Bogi

doi:10.1074/jbc.m117.793117

Cited by 28 publications

(26 citation statements)

References 55 publications

(53 reference statements)

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“…Interestingly, we have found the 9aaTAD activation domain in Crassostrea gigas, KLF1 ortholog (9aaTAD sequence ELL DYD FIL, gene ID; EKC39171), which closely resembles the first identified 9aaTAD in activator Oaf1 (9aaTAD sequence DLF DYD FLF) (12). Surprisingly, the 9aaTAD activation domains of KLF3 and KLF8 did not activate transcription, which correlated with their repressor function reported previously (52,(81)(82)(83)(84). The accumulation of valines has been shown here again to be associated with the 9aaTAD deactivation (Figures 7).…”

Section: Klf Homology With the Sp Family Revealed Their Activation Dosupporting

confidence: 76%

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček

Havelka

Jendruchova

et al. 2019

Preprint

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The Sp1 transcription factor has been defined as glutamine-rich activator. The Nine amino acid TransActivation Domains (9aaTAD) have been identified in numerous transcription activators. Here, we identified the conserved 9aaTAD motif in the Sp1 and in all nine members of SP family with broad natural 9aaTAD variations. We showed by the amino acid substitutions that the glutamine residues are completely dispensable for 9aaTADs function. We described the 9aaTAD domains' origin and evolutionary history. The ancestral Sp2 gene with inactive 9aaTAD has duplicated in early chordates and created new paralogs Sp1, Sp3 and Sp4. We discovered that the accumulation of valines in the 9aaTADs correlated with the domain inactivation. The Sp2 activation domain, whose dormancy have lasted over 100 million years during chordate evolution, enabled later diversification in the Sp1-4 clade, including both repressors and activators. The new paralogs Sp1 and Sp3 activation domains have regained their original activator function by loss of valines in their 9aaTADs.Keywords: activation domain, 9aaTAD, SP, Sp1, KLF, WT1, Gal4, Met4, Gcn4 and p53. demonstrated the importance of the hydrophobic amino acids for Gcn4 (30-33) and p53 activators (8,(34)(35)(36)(37)(38)(39)(40). Similarly, in the original report for the glutamine-rich activator Sp1(41), the importance of hydrophobic amino acids was already recognized, regardless of the overrepresented glutamines.Nevertheless, the designation as acidic or glutamine-rich activation domains persists to date (42-49).In the human genome, there are about 1,691 annotated transcription factors, divided into 68 groups according to their conserved DNA binding domain (50). The C2H2-type zinc finger is the largest group (682 members), which includes the evolutionally conserved family of KLF activators (Krüppel-like factors). The SP activators (Specificity proteins Sp1-9) belong to a new evolutional branch derived from the ancestral KLF family. The SP activators have been linked to cell proliferation, embryonic development, tissue differentiation, Wnt signaling pathway, metabolism, and their dysregulation has been implicated in a number of human diseases and cancers (51)(52)(53)(54)(55)(56). This report has focused on the SP family and followed the 9aaTAD domain's evolution. MATERIALS AND METHODSConstructs. The construct pBTM116-HA was generated by an insertion of the HA cassette into the EcoRI site of the vector pBTM116. The constructs G1-G45 and H1-H45 were generated by PCR and sub-cloned into pBTM116 EcoRI and BamHI sites. All constructs have a spacer of three amino acids inserted into the EcoRI site; peptide GSG. All constructs have been sequenced by Eurofins Genomics.Further detailed information about constructs and primer sequences are available on request.Assessment of enzyme activities. The β-galactosidase activity was determined in the yeast strain L40 (57,58). The strain L40 has a chromosomally integrated lacZ reporter driven by the lexA operator. In all hybrid assays, we used 2μ vector pBTM116 for...

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Section: Klf Homology With the Sp Family Revealed Their Activation Dosupporting

confidence: 76%

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček

Havelka

Jendruchova

et al. 2019

Preprint

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“…Notably, skin and mammary gland epithelium are both derived from the ectodermal lineage and they may share similar transcription profiles and functions. However, grouping the cell types based on SEs displayed less similarity than TEs, which indicated a unique role of SEs in cell identity as compared to the TEs . Collectively, these data provide detailed functional evidence on how genomic organization regulates cell‐specific transcriptional programmes.…”

Section: Higher Order Chromatin Remodelers In Skin Development and Homentioning

confidence: 92%

“…[96] However, the question remains how the SEs and TEs. [97] Collectively, these data provide detailed functional evidence on how genomic organization regulates cell-specific transcriptional programmes.…”

Section: Hi G Her Order Chromatin Remodeler S In S K In De Velopmenmentioning

confidence: 95%

Epigenetic control in skin development, homeostasis and injury repair

Kang

Chovatiya

Tumbar

2019

Experimental Dermatology

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Cell‐type‐ and cell‐state‐specific patterns of covalent modifications on DNA and histone tails form global epigenetic profiles that enable spatiotemporal regulation of gene expression. These epigenetic profiles arise from coordinated activities of transcription factors and epigenetic modifiers, which result in cell‐type‐specific outputs in response to dynamic environmental conditions and signalling pathways. Recent mouse genetic and functional studies have highlighted the physiological significance of global DNA and histone epigenetic modifications in skin. Importantly, specific epigenetic profiles are emerging for adult skin stem cells that are associated with their cell fate plasticity and proper activity in tissue regeneration. We can now begin to draw a more comprehensive picture of how epigenetic modifiers orchestrate their cell‐intrinsic role with microenvironmental cues for proper skin development, homeostasis and wound repair. The field is ripe to begin to implement these findings from the laboratory into skin therapies.

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“…Members of the KLF gene family regulate cell proliferation, differentiation and survival, and have been found to play a role in airway inflammation (43). In particular, KLF7 is involved in regulating epithelial cell differentiation and epithelial-mesenchymal transition (44, 45), and possibly in airway remodeling (46).…”

Section: Discussionmentioning

confidence: 99%

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene

Saferali

Yun

Parker

et al. 2019

Preprint

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While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD).RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 60% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1×10−6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2.Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.Author SummaryWhile it is known that chronic obstructive pulmonary disease (COPD) is caused in part by genetic factors, few studies have identified specific causative genes. Genetic variants that alter the expression levels of genes have explained part of the genetic component of COPD, however, there are additional genetic variants with unknown function. In some genes the protein coding sequence can be altered by a mechanism known as RNA splicing. We hypothesized that some genetic variants that are associated with risk of COPD contribute to the disease by altering RNA splicing. In this study, we identified genetic variants that are associated both with COPD risk and RNA splicing. In particular, we found that a COPD associated variant of previously unknown function may contribute to the inclusion of a new exon in the FBXO38 gene. These finding are significant because they indicate that analysis of RNA splicing can help identify genes that contribute to disease.

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Characterization of enhancers and the role of the transcription factor KLF7 in regulating corneal epithelial differentiation

Cited by 28 publications

References 55 publications

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Epigenetic control in skin development, homeostasis and injury repair

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene

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