Trans-Regulatory KLF14 Gene: Comparison
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Krüpple-Like family of transcription factor-14 (KLF14) is a master trans-regulatory gene that has multiple biological regulatory functions and is involved in many pathological mechanisms. It controls the expressions of several other genes which are involved in multiple regulatory functions. 

  • KLF14 gene
  • single nucleotide polymorphism
  • genetic variations
  • ApoA1
  • KLF14 gene polymorphism

1. Introduction

KLF14 is a member of the Krüpple-Like family of transcription factors [1,2][1][2], which regulates normal gene expression in mammals. In total, there are eighteen KLF proteins that are further grouped into three families. KLF14 activates transcription but also possesses a repressive role by interacting with Sin3A, which is a co-repressive protein in DNA [1]. KLFs have different patterns of expression in different body tissues by which many exhibit pronounced expressions, including KLF6 [3], KLF7 [4], KLF9 [5], KLF10 [6], KLF11 [7], KLF13 [8], and KLF15 [9]. While some members have tissue-specific expression, e.g., KLF1 expresses in megakaryocytes and red blood cells, KLF2 expresses in white adipose tissues, and KLF4 and KLF5 express in blood vessels and white adipose tissues [10].
KLF14 is a master trans-regulatory gene linked with the expression of various multiple metabolic traits. Mutations in master regulatory genes are often linked with the incidence of severe diseases as these genes regulate the concurrent expression of several genes [11]. Several kinds of metabolic disorders, including diabetes mellitus (DM), cardiovascular diseases (CVDs), and especially coronary artery diseases (CADs), are strongly linked with the variants near the KLF14 gene which is located on chromosome 7. KLF14 variants have more frequent expressions in women than in men. It has been evidenced from several studies that environmental factors directly influence the normal expression of the KLF14 gene and play a significant role in altered metabolic processes [10].
KLF proteins regulate several cell signaling pathways, including apoptosis, proliferation, and differentiation, etc. [1]. Only the maternal allele of KLF14 is expressed in humans and KLF14 expression has been found in many organs and tissues, including adipose tissues, the liver, the brain, and muscles [12]. KLF14 regulates insulin secretion, lipid metabolism, inflammatory responses, cell differentiation, and proliferation. Therefore, it is proven as a potential target to reduce the risk of CVDs [13]. Moreover, KLF14 regulates the efflux of HDL-C and ApoA-1; therefore, alterations in the normal expression of KLF14 triggered by gene polymorphism or epigenetic alteration induce the onset of metabolic disorders [14]. Several KLF14 variants have been identified using genome-wide association studies (GWASs), which lead toward the altered insulin sensitivity, development, and progression of several metabolic diseases, including DM, myocardial infarction, atherosclerotic cardiac diseases, and ischemic stroke [15,16,17,18][15][16][17][18]. Interestingly, single-nucleotide polymorphisms (SNPs) of KLF14 were significantly found in adipose tissues [15,19][15][19]. KLF14 has different CpG sites which can be hypermethylated over age, thus KLF14 can be used to estimate the chronological age and serve as an age-related epigenetic biomarker [20]. KLF14 is widely expressed in various tissues, and its role in different altered metabolic processes has been reviewed. Researchers have previously worked on genetic polymorphism of different genes, including FTO, PPAR-γ, ABCC8, APOEε4, AGT, and MTHFR genes [21,22,23,24][21][22][23][24]. 

2. Configuration and Expression of the KLF14 Gene

KLF proteins bind with the regulatory regions of a targeted gene as these proteins have conserved C2H2-type zinc finger domains at their C-terminal, which is involved in binding with the GC-rich regions of the genes [1]. The KLF14 protein retains three C2H2-type zinc finger structural motifs in C-terminus with two domains (first and second) and a short third domain encompassing 25 and 23 amino acid residues, receptively [25,26][25][26]. These three zinc finger domains can identify three DNA base pairs, and thus have an affinity to bind at three sites in the gene regulatory region [27]. Moreover, it has been found that these domains possess positively charged amino acids which may assist in the localization of the nucleus. Several investigational studies concluded that KLF proteins can interact with similar GC-rich sequences or 5′-CACCC-3′ of several genes’ promoter regions [28,29][28][29]. KLF proteins show binding affinity with other proteins’ associates such as co-repressors, histone-modifying enzymes, and co-activators, etc., due to their N-terminus regions [30].
The transcriptional target sites of KLF14 are not well described however, few studies have identified different targets. Liver-specific KLF14 knockout in mouse models causes ApoA-1 deficiency, which indicates that KLF14 is involved in the transcriptional regulation of ApoA-1 [31]. Therefore, ApoA-1 is an important target of KLF14. There are two binding sites for KLF14 on the promoter region of ApoA-1 in humans. Sphingosine kinase 1 (SK1) is also a functional transcriptional target of KLF14. KLF14 suppresses the transcription of SK1 by binding with its promoter region [32]. One study demonstrated that KLF14 at the FOXP3 Treg-specific demethylation region remolds the chromatin and, as a result, regulates T-cell differentiation [33].
Trans-regulated genes’ promoter regions have enriched binding motifs for KLF14 [10]. These trans-genes regulate the MetSyn such as IDE, a regulator of insulin degradation [34], SLC2A4, which regulates the expression of GLUT4 protein which is responsible for insulin-induced glucose uptake in muscles and adipose tissues [35], and STARD10 which regulates insulin secretion in β-cells of pancreatic islets [36,37][36][37] as shown in Table 1. Moreover, KLF14 regulates the MAPK proteins level as KLF14 knockout results in the elevated level of MAPK proteins, including p38 and ERK1/2, which are associated with the regulation of several pro-inflammatory factors [38].
Table 1.
Impact and ultimate consequences of KLF14 genetic variants on Trans-regulatory genes.
Sr.# Tans- Regulator Gene Gene Encoded Protein Gene Expression KLF14 Interaction Mutant KLF14 Impact on Gene Expression Consequences Ref.
1. IDE Zinc metallopeptidase (Insulin degrading enzyme) IDE degrades peptides, including insulin, glucagon, and amylin. Moreover, it regulates pancreatic β cells functions KLF14 binds with promoter site of IDE gene Impaired KLF14 induces irregularities in the normal IDE gene expression Ultimate outcomes are glucose intolerance, impaired insulin degradation, insulin resistance, and type 2 diabetes mellitus inducement [10,39][10][39]
2. SLC2A4 GLUT4 Regulates the insulin sensitive facilitative glucose transportation in fats and muscle cells The promoter region of SLC2A4 gene has binding affinity for KLF14 KLF14 regulates the SLC2A4 normal expression, any genetic variations in KLF14 lead toward compromised SLC2A4 gene expression in glucose regulation Glucose intolerance which leads to type 2 diabetes mellitus development and obesity [10,40][10][40]
3. STARD10 StAR-related lipid transfer protein 10 This phosphoinositide-binding protein regulates insulin secretion and synthesis KLF14 has an affinity to bind with the promoter region of the STARD10 trans-gene Mutant KLF14 binding on the promoter region of the gene increases the risk of type 2 diabetes mellitus by disrupting the normal gene expression Glucose intolerance, impaired glucose-induced insulin secretion, and type 2 diabetes mellitus [10,41][10][41]

3. KLF14 Trans-Regulatory Network

The KLF14 gene is located on chromosome 7q32.3. Out of 82 KLF14-linked transcriptional factors, only 62 have been identified in humans. Transcriptional factors are specialized proteins that control gene expression. These factors are encoded by different genes, including HOXA9, HOXA3, and AHR. The Sin2A protein represses transcription, which leads to the transcriptional repression of important enzymatic proteins such as HDAC1 and HDAC2, DNA binding proteins, such as Mas and MeCP2, and the co-repressor proteins Ikaros and SMRT [42,43][42][43].
The major family of transcriptional factors, including sequence-specific DNA proteins and genes, have an important role in the regulation of different body functions, including CNS development (EN1), hematopoiesis (EVI1), cell growth regulation (MEF2A), regeneration of muscle (MYOD1), cell apoptosis (EVI1, MEF2A), and erythroid development (GATA1), and are vital in normal growth (MEIS1), hematopoietic proliferation and development, and endocrine cell lineage (GATA2), and embryonic regulation (FOXC1), etc. Interestingly, important genes that are involved in the pathogenesis of metabolic disorders such as the TCF7L2 and PPARG genes are not included among these genes.
The trans-acting regulator, encoded by the KLF14 gene regulates the expression of a cluster of genes that are involved with the metabolic phenotypes, including HDL level, insulin and glucose levels, LDL level, TG level, BMI, and insulin sensitivity index, etc. [11]. The resultant product (transcriptional factor) of KLF14 gene transcription interacts with 10 genes and establishes the protein–protein interactions with 32 proteins, which have a strong association with metabolic disorders and several other biological functions [44]. These 32 proteins, including CKAL1, KCNQ1, IGF2BP2, etc., have shown significant interaction with the KLF14 protein. Studies have shown that the KLF14 protein interacts with UBC (polyubiquitin precursor) which regulates the cell cycle, endocytosis, apoptosis, cell signaling pathways, DNA repair, and protein trafficking, etc. [11].

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