Epigenetics of human development
Epigenetics play an important role in animal development, including the development of human beings. Various epigenetic markers serve different roles that faciliate the growth of human organisms.
Definitions
Hox gene regulation
s are genes in humans that regulate body plan development. Humans have four sets of Hox genes, numbering 39 genes altogether, all of which aid in the differentiation of cells by location. Hox genes are activated early in the development of the embryo, in order to plan the development of the differing structures of the body. They also show colinearity with the body plan, meaning that the order of the Hox genes is similar to the expression levels of the Hox genes on the anterior-posterior axis. This colinearity allows for a spatial and temporal activation of genes in order to produce a proper body structure.In Hox genes, long non-coding RNAs allow for communication between different Hox genes and different sets of Hox genes in order to coordinate body plan in the cell. One example of a long non-coding RNA that coordinates between Hox gene sets is HOTAIR, which is an RNA transcript produced in the HoxC cassette that represses transcription of a large number of genes in the HoxD cassette. Thus, HOTAIR regulates the HoxD genes from the HoxC genes in order to coordinate transcription of the Hox genes.
Role of PcG and TrxG
The PcG and TrxG genes that produce protein complexes responsible for continuing the activation and the repression patterns in the Hox genes initially formed by the maternal factors. PcG genes are responsible for repressing chromatin in Hox clusters meant to be inactivated in the differentiated cell. PcG proteins repress genes by forming polycomb repressive complexes, such as PRC1 and PRC2. PRC2 complexes repress by trimethylating histone 3 at lysine 27 through histone methyltransferases Ezh2 and Ezh1. PRC2 is recruited by many elements, including CpG islands. PRC1, meanwhile, ubiquitinates H2AK119 using Ring1A/B's E3 ligase activity, causing stalling of RNA polymerase II. Furthermore, Ring1B, a member of the PRC1 complex, also represses Hox genes with Me118, Mph2, and RYBP by compacting the chromatin into higher-order structures. TrxG genes, meanwhile, are responsible for activating genes by trimethylating lysine 4 of the histone H3 tail. Genes with similar transcriptional marks tend to cluster together in distinct structures. In bivalent domains, both of these marks are present, indicating genes that are silenced but can be rapidly activated when necessary.Role of ncRNAs
231 ncRNAs are present in the four Hox gene cassettes. Similarly to the Hox protein-coding genes, the ncRNAs show differential expression according to the cell's location on the anterior-posterior and proximal-distal axes. These lncRNAs can act either on the set of genes which they are present in, or can act on a separate gene set within the Hox genes.HOTTIP is a long non-coding RNA that assists in regulating the HoxA genes. It is produced from the 5' end of the HoxA gene cassette, and activates HoxA genes. Loops within the chromosome bring HOTTIP closer to its targets; this allows HOTTIP to bind to WDR5/MLL protein complexes to aid in trimethylation of lysine 4 of histone 3.
HOTAIR is a long non-coding RNA that assists in regulating the HoxD genes. It is produced in the HoxC cassette, near the divide between expressed and unexpressed genes, and represses HoxD genes. HOTAIR acts by attaching to Suz12 in the PRC2 complex, and then guides this complex to the genes to be repressed. PRC2 then trimethylates the lysine 27 of histone 3, repressing the gene of interest.
Barr body formation
In female humans, Barr bodies are defined as the condensed and inactivated X-chromosome that is found in every cell of the adult. Because females have two nearly identical X chromosomes, one of them must be silenced so that the expression levels of the genes on the X-chromosome are of the proper dosage. Thus, males and females have the same level of X-chromosome expression, despite being born with one X for males and two for females. This is also why individuals with Klinefelter syndrome, a disease in which more than two sex chromosomes are present in the body, have fewer symptoms than individuals with other types of aneuploidy, which are often fatal before birth.Role of Xist
of one of the X chromosomes is initiated by a long non coding RNA called Xist. This lncRNA is expressed on the same chromosome it represses, known as working in cis. Recent research has shown that a repeat element in the RNA of Xist causes PRC2 to bind to the RNA. Another part of the RNA binds to the X-chromosome positioning PRC2 such that it can methylate various regions on the X-chromosome. This methylation causes other factors like histone deacetylases to bind to the chromosome and propagate heterochromatin formation, even into active gene regions. This heterochromatin greatly reduces, if not completely silences gene expression of the Barr body. Xist will be continuously created to maintain a condensed and silenced Barr body.In human cells with more than one X chromosome, two long non-coding RNAs are produced: Tsix is produced by one X chromosome, and Xist is produced by all of the other X chromosomes. Tsix is a long non-coding RNA that prevents repression of an X chromosome, while Xist is a long non-coding RNA that acts to repress and condense an entire X chromosome. The actions of Xist serve to create a Barr body in the cell.
Random early X-chromosome inactivation
Imprinting
is defined as the differential expression of paternal and maternal alleles of a gene, due to epigenetic marks introduced onto the chromosome during the production of egg and sperm. These marks usually lead to differential expression of the specific sets of genes from the maternal and paternal chromosomes. Imprinting is carried out through many epigenetic mechanisms like methylation, histone modifications, rearrangement of higher order chromatin structure, non-coding RNAs, and interfering RNAs.Function
A single evolutionary purpose of imprinting is still unknown, since the mechanisms and effects seem to be so diverse. One hypothesis states that imprinting occurs in order to carry out the evolutionary goal of the parent, that being the differential partition of resources. The male seeks to provide maximum resources for his offspring so that his genes may be passed on successfully to the next generation, whereas the female must partition resources between all her offspring, and so must limit resources given.Another hypothesis states that imprinting may help protect the female from ovarian trophoblastic disease and parthenogenesis. Trophoblastic disease occurs when a sperm fertilizes an egg with no nucleus and a cancer-like mass forms in the placenta. Parthenogenesis occurs when an unfertilized egg develops into a fully functional organism that is genetically identical to the parent, who is female in the case of animals or both sexes, in the case of plants.
Igf2 and H19
In mammals, imprinted genes are often clustered in the genome, probably because they share transcriptional regulators or regulatory regions that impact the expression of multiple genes. It is easier for a lncRNA to silence multiple genes if they are closer together, making silencing more efficient. In some cases, when a gene is transcribed it overlaps another region nearby or opposite to it, often silencing it. In the case of the Ifg2 and H19 genes, CTCF, a transcriptional repressor protein, is involved. CTCF binds to the unmethylated maternal ICR region but not the methylated paternal ICR region. ICR is a shared control region of Ifg2 and H19 that, when deleted, results in the loss of imprinting of these genes. CTCF then binds another region of the chromosome, creating a loop where Igf2 is blocked from transcription, but H19 is not, resulting in the maternal chromosome expressing H19 but not Igf2. CTCF has been shown to directly interact with Suz12, a subunit of PRC2, in order to silence the Ifg2 promoter region through hypermethylation. Conversely, the paternal H19 promoter is highly methylated during embryogenesis so that Ifg2 will not be silenced. Should CTCF fail to bind, H19 on the maternal chromosome has reduced expression and Igf2 is not silenced properly, resulting in biallelic expression. Mice have homologues of these genes, but silence them in a different way, where biallelic expression occurs and then antisense RNA is used to silence one of the genes.Igf2r and Airn
is an lncRNA used to silence Igf2r and other surrounding genes. In the mechanism to silence Igf2r, the transcription of the lncRNA Airn silences the expression of Igf2r, as opposed to an active repression mechanism. Airn is the antisense gene of Ifg2r, so if Airn is being transcribed, the transcriptional machinery may cover a part of or the entire promoter region of Igf2r, so RNA polymerase cannot bind to the promoter region of Igf2r in order to initiate transcription. This mechanism is very efficient in that Igf2r is silenced by transcription of Airn, while the RNA product silences other genes near Igf2r. The imprinting mechanisms described above work on the chromosome that the Airn lncRNA is produced, but there are many other imprinted genes that work to silence genes on other chromosomes or to silence the similar allele on the opposing chromosome of the same pair. Some imprinted genes code for regulatory RNA elements such as lncRNA, small nucleolar RNA, and micro RNA, so the expression of these genes results in the silencing of some other gene.From these examples, researchers have seen similar patterns in developmental genetics. It is imperative that many genes are silenced at the right time so that cells can maintain their identity and expressional integrity. Failure to do so often leads to symptoms such as cognitive abnormalities, if not fatality.