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Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the mother or the father. Genes can also be partially imprinted. Partial imprinting occurs when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parent's allele. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. In 2014, there were about 150 imprinted genes known in mice and about half that in humans. As of 2019, 260 imprinted genes have been reported in mice and 228 in humans.
The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the nuclear genome and the mitochondrial genome. Human genomes include both protein-coding DNA sequences and various types of DNA that does not encode proteins. The latter is a diverse category that includes DNA coding for non-translated RNA, such as that for ribosomal RNA, transfer RNA, ribozymes, small nuclear RNAs, and several types of regulatory RNAs. It also includes promoters and their associated gene-regulatory elements, DNA playing structural and replicatory roles, such as scaffolding regions, telomeres, centromeres, and origins of replication, plus large numbers of transposable elements, inserted viral DNA, non-functional pseudogenes and simple, highly repetitive sequences. Introns make up a large percentage of non-coding DNA. Some of this non-coding DNA is non-functional junk DNA, such as pseudogenes, but there is no firm consensus on the total amount of junk DNA.
Prader–Willi syndrome (PWS) is a genetic disorder caused by a loss of function of specific genes on chromosome 15. In newborns, symptoms include weak muscles, poor feeding, and slow development. Beginning in childhood, those affected become constantly hungry, which often leads to obesity and type 2 diabetes. Mild to moderate intellectual impairment and behavioral problems are also typical of the disorder. Often, affected individuals have a narrow forehead, small hands and feet, short height, and light skin and hair. Most are unable to have children.
A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-coding RNAs include transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as small RNAs such as microRNAs, siRNAs, piRNAs, snoRNAs, snRNAs, exRNAs, scaRNAs and the long ncRNAs such as Xist and HOTAIR.
Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.
Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 99.7 million base pairs and represents between 3% and 3.5% of the total DNA in cells. Chromosome 15 is an acrocentric chromosome, with a very small short arm, which contains few protein coding genes among its 19 million base pairs. It has a larger long arm that is gene rich, spanning about 83 million base pairs.
In molecular biology, Small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs. There are two main classes of snoRNA, the C/D box snoRNAs, which are associated with methylation, and the H/ACA box snoRNAs, which are associated with pseudouridylation. SnoRNAs are commonly referred to as guide RNAs but should not be confused with the guide RNAs that direct RNA editing in trypanosomes or the guide RNAs (gRNAs) used by Cas9 for CRISPR gene editing.
Polar overdominance is a unique form of inheritance originally described in livestock, with relevant examples in humans and mice being discovered shortly after. The term polar is used to describe this type of overdominance because the phenotype of the heterozygote is more prevalent than the other genotypes. This polarity is shown as differential phenotype is only present in one of the heterozygote configurations when the recessive allele is inherited in a parent of origin type fashion. Polar overdominance differs from regular overdominance where both heterozygote genotypes display a phenotype that has increased fitness regardless of the parent of origin. Studying this type of inheritance could have practical applications in preventative medicine for humans as well as a variety of other agricultural applications.
In molecular biology, SNORD116 is a non-coding RNA (ncRNA) molecule which functions in the modification of other small nuclear RNAs (snRNAs). This type of modifying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis. It is known as a small nucleolar RNA (snoRNA) and also often referred to as a guide RNA.
H19 is a gene for a long noncoding RNA, found in humans and elsewhere. H19 has a role in the negative regulation of body weight and cell proliferation. This gene also has a role in the formation of some cancers and in the regulation of gene expression. .
KCNQ1 overlapping transcript 1, also known as KCNQ1OT1, is a long non-coding RNA gene found in the KCNQ1 locus. This locus consists of 8–10 protein-coding genes, specifically expressed from the maternal allele, and the paternally expressed non-coding RNA gene KCNQ1OT1. KCNQ1OT1 and KCNQ1 are imprinted genes and are part of an imprinting control region (ICR). Mitsuya identified that KCNQ1OT1 is an antisense transcript of KCNQ1. KCNQ1OT1 is a paternally expressed allele and KCNQ1 is a maternally expressed allele. KCNQ1OT1 is a nuclear, 91 kb transcript, found in close proximity to the nucleolus in certain cell types.
Long non-coding RNAs are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Long intervening/intergenic noncoding RNAs (lincRNAs) are sequences of lncRNA which do not overlap protein-coding genes.
MEG3 is a maternally expressed, imprinted long non-coding RNA gene. At least 12 different isoforms of MEG3 are generated by alternative splicing. Expression of MEG3 is lost in cancer cells. It acts as a growth suppressor in tumour cells, and activates p53. A pituitary transcript variant has been associated with inhibited cell proliferation. Studies in mouse and sheep suggest that an upstream intergenic differentially methylated region (IG-DMR) regulates imprinting of the region. The expression profile in mouse of the co-regulated Meg3 and Dlk1 genes suggests a causative role in the pathologies found in uniparental disomy animals, characterized by defects in skeletal muscle maturation, bone formation, placenta size and organization and prenatal lethality. The sheep homolog is associated with the callipyge mutation which in heterozygous individuals affects a muscle-specific long-range control element located in the DLK1-GTL2 intergenic region and results in the callipyge muscular hypertrophy. The non-Mendelian inheritance pattern, known as polar overdominance, likely results from the combination of the cis-effect on the expression levels of genes in the DLK1-GTL2 imprinted domain, and trans interaction between the products of reciprocally imprinted genes.
In molecular biology, Small nucleolar RNA SNORD113 is a small nucleolar RNA molecule which is located in the imprinted human 14q32 locus and may play a role in the evolution and/or mechanism of the epigenetic imprinting process.
mir-127 microRNA is a short non-coding RNA molecule with interesting overlapping gene structure. miR-127 functions to regulate the expression levels of genes involved in lung development, placental formation and apoptosis. Aberrant expression of miR-127 has been linked to different cancers.
In molecular biology, Maternally expressed 8, also known as MEG8 or Rian, is a long non-coding RNA. It is an imprinted gene, which is maternally expressed. It is expressed in the nucleus and is preferentially expressed in skeletal muscle.
In molecular biology, MEST intronic transcript 1, antisense RNA, also known as MESTIT1 or PEG1-AS is a long non-coding RNA. It is an imprinted gene, which is paternally expressed. In humans, it is found on chromosome 7q32, imprinted genes on chromosome 7 are believed to be involved in Russell-Silver syndrome (RSS). However, it is believed that MESTIT1 is unlikely to cause Russell-Silver syndrome as there is a lack of mutations in this gene in Russell-Silver syndrome patients. MESTIT1 may regulate the expression of the MEST gene.
Joomyeong Kim is a Russell Thompson, Jr. Family Professor of Biology at Louisiana State University. His research interests include genomic imprinting and epigenetics. Dr. Kim's laboratory is mainly involved in understanding the functions and regulatory mechanisms governing genes subject to genomic imprinting. Having previously characterized an imprinted domain located on proximal mouse chromosome 7/ human chromosome 19q13.4, his laboratory currently focuses on understanding regulatory mechanisms directing the mono-allelic expression of the seven imprinted genes in the cluster: Peg3, Usp29, Zfp264, APeg3 and Zim1, Zim2, Zim3. As a second project direction, his lab studies the function of the dominant gene in the cluster, Peg3, as a transcriptional regulator. Past projects in the Kim lab have included studying the epigenetic instability of imprinted genes during tumorigenesis, potential roles of AEBP2 as a PRC2 targeting protein and in neural crest cell development, as well as the DNA methylation of mouse and human retrotransposons.
Epigenetics of human development is the study of how epigenetics effects human development.
See also:RNA therapeutics and Messenger RNA
References
- ↑ Kim, J.; Bergmann, A.; Choo, J. H.; Stubbs, L. (2007). "Genomic organization and imprinting of the Peg3 domain in bovine". Genomics. 90 (1): 85–92. doi: 10.1016/j.ygeno.2007.03.012 . PMID 17509818.
- ↑ Flisikowski, K.; Venhoranta, H.; Nowacka-Woszuk, J.; McKay, S. D.; Flyckt, A.; Taponen, J.; Schnabel, R.; Schwarzenbacher, H.; Szczerbal, I.; Lohi, H.; Fries, R.; Taylor, J. F.; Switonski, M.; Andersson, M. (2010). Roberts, Roland G. (ed.). "A Novel Mutation in the Maternally Imprinted PEG3 Domain Results in a Loss of MIMT1 Expression and Causes Abortions and Stillbirths in Cattle (Bos taurus)". PLOS ONE. 5 (11): e15116. Bibcode:2010PLoSO...515116F. doi: 10.1371/journal.pone.0015116 . PMC 2994898 . PMID 21152099.