Zinc finger protein 226 is a protein that in humans is encoded by the ZNF226 gene.
Gene The zinc finger protein 226 is also known as the Kruppel-associated box protein. Within humans, the ZNF226 gene is found on the plus strand of chromosome19q13, spanning 13,311 nucleotides from 44,165,070 to 44,178,381.
Transcript Currently, there are 20 different transcript variants encoding ZNF226. All of them have six or seven identified exon regions within ZNF226. The longest identified transcript, ZNF226 transcript variant x4 spans 2,797 base pairs (bp).
Protein ZNF226 is currently known to have three isoforms within humans: ZNF226 isoform X1, ZNF226 isoform X2, and ZNF226 isoform X3. The ZNF226 isoform X1 protein is the longest known variant, with 803 amino acids. This protein contains the Kruppel associated box A (KRAB-A) domain, which functions as a transcriptional repressor. However, the exact function of the ZNF226 protein is currently unknown. Within isoform X1, there are 18 Cys2His2 zinc finger structural motif (zf-Cys2His2) domains, which are known to bind either zinc ions (Zn2+) or nucleic acid (Figure 7–8). Within those regions, cysteine and histidine are the primary amino acids that bind to Zn2+ or nucleic acid, although other amino acids have been identified for binding (Figure 7–8). In addition to the KRAB-A domain and zf-Cys2His2 domains, there are zinc finger double domains which also contain binding sites for ions or nucleic acids. ZNF226 human and ortholog protein sequences have molecular weights between 89 and 92 kDa. They had isoelectric points (pI) ranging from 8.60 to 9.00. In humans, the zf-Cys2His2 and zinc finger double domain region of ZNF226 isoform X1 is 59.3 kDa with a theoretical pI of 9.11. With the spacing of cysteine, or C, there is a cysteine every three amino acids. At least one of the amino acids in between the C's are either aspartic acid or glutamic acid. Despite the region's patterns of aspartic acid, it is still considered to have a lesser amount of the amino acid at 1.9%. There is also repetition within the chemical patterns within humans that is characteristic of ZNF226. These repetitions appear most common within the zf-Cys2His2 and zinc finger double domains of the protein, notably with cysteine and histidine binding sites. Predicted secondary structures of ZNF226 demonstrate a variable number of alpha helices, beta-stranded bridges, and random coils throughout the protein. Using various programs, such as GOR4 and the Chou and Fasman program, there is overall similarity in the predictions of coiled, stranded, and helix regions throughout the protein.
Regulation
Gene
Promoter Using the Genomatix software, GXP_7536741 (1142 bp) was identified as the best promoter of ZNF226 (Figure 1). Within the last 500 bp of the promoter, the signal transducer and activator of transcription (V$STAT.01), selenocysteine tRNA activating factor (V$THAP11.01), and cell cycle regulators: cell cycle homology region (V$CHR.01) were conserved among Homo sapiens, Macaca mulatta, Pan troglodytes, and Canis lupus familiaris. In addition, the SPI-1 proto-oncogene; hematopoietic TF PU.1 (V$SPI1.02) was also known for binding to a promoter region within the c-fes proto-oncogene which encodes tyrosine kinase. The TF binding site is also found in two regions within the promoter sequence. The signal transducer and activator of transcription binding site was also conserved in two regions, and is known to have a higher binding specificity. The selenocysteine tRNA activating factor plays a role in embryonic stem cell regeneration. The cell cycle regulators: cell cycle homology region binding site plays an important role in cell survival, where mutations in the transcription factor can lead to apoptosis.
Tissue distribution In terms of gene expression, ZNF226 is generally expressed in most tissues. Microarray data illustrates higher expression of ZNF226 within the ovaries. This is further supported by data which depicts a decrease in ZNF226 expression in granulosa cells within individuals with polycystic ovary syndrome. There was also higher expressions of ZNF226 observed within the thyroid compared to other tissues. Evidence of decreased ZNF226 expression is observed with individuals with papillary thyroid cancer. Within fetuses, there is some level of ZNF226 expression present within all tissues throughout the gestational period of 10 to 20 weeks. However, there is a higher level of ZNF226 expression in the heart at 10 weeks of gestation, and a decreased level of expression within kidneys at 20 weeks gestation. ZNF226 expression has been observed within epithelial progenitor cells (EPCs) in the peripheral blood (PB) and umbilical cord blood (CB). The gene expression is lower in PB-EPCs when compared to CB-EPCs. PB-EPCs have more tumor suppressor (TP53) expression when compared to CB-EPCs. CB-EPCs have more angiogenic expression, or growth and splitting of vasculature.
Transcript Using RNAfold, minimum free energy structures were created based on the extended 5' and 3' untranslated region (UTR) in human sequences. Unconserved amino acids, miRNA, stem-loop formations, and RNA binding proteins (RBPs) are shown on the diagram (Figure 2–3).
miRNA targeting Within the 5' UTR region, both miR-4700-5p and miR-4667-5p were referenced in an experiment which identified certain miRNAs expressed consistently in ERBB2+ breast cancer gene. In addition, miR-8089 was referenced in a study showing certain novel miRNAs found within sepsis patients. miR-4271 was shown to have effects on coronary heart disease binding to the 3' UTR region of the APOC3 gene. Literature on miR-7113-5p shows that this miRNA is a mirtron. Within the 3' UTR region, miR-3143 is referenced in a study where miRNAs were expressed consistently in ERBB2+ breast cancer gene. miR-152-5p plays a role in inhibiting DNA methylation of genes involved in metabolic and inflammatory pathways. miR-31-3p is overexpressed in esophageal squamous cell carcinoma (ESCC). One miRNA result, miR-150-5p, was conserved across multiple homologs within the 3' UTR region more than 3000 bp downstream. The miR-150-5p miRNA plays a role in colorectal cancer (CRC), where a lower expression of the miRNA was associated with a suppression of CRC metastasis.
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