what level of transcription would you predict for a gene whose promoter is heavily methylated?

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The Role of DNA Methylation and Histone Modifications in Transcriptional Regulation in Humans

Subcell Biochem. Author manuscript; available in PMC 2019 Jul 5.

Published in final edited form as:

Subcell Biochem. 2013; 61: 289–317.

doi: 10.1007/978-94-007-4525-4_13

PMCID: PMC6611551

NIHMSID: NIHMS1007331

PMID: 23150256

The Role of DNA Methylation and Histone Modifications in Transcriptional Regulation in Humans

Jaime L. Miller and Patrick A. Grant

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Abstract

Although the field of genetics has grown by leaps and bounds within the last decade due to the completion and availability of the human genome sequence, transcriptional regulation still cannot be explained solely by an individual’s DNA sequence. Complex coordination and communication between a plethora of well-conserved chromatin modifying factors are essential for all organisms. Regulation of gene expression depends on histone post translational modifications (HPTMs), DNA methylation, histone variants, remodeling enzymes, and effector proteins that influence the structure and function of chromatin, which affects a broad spectrum of cellular processes such as DNA repair, DNA replication, growth, and proliferation. If mutated or deleted, many of these factors can result in human disease at the level of transcriptional regulation. The common goal of recent studies is to understand disease states at the stage of altered gene expression. Utilizing information gained from new high-throughput techniques and analyses will aid biomedical research in the development of treatments that work at one of the most basic level of gene expression, chromatin. This chapter will discuss the effects of and mechanism by which histone modifications and DNA methylation affect transcriptional regulation.

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1.1. DNA Methylation

1.1.1. CpG Islands

With respect to epigenetic research and a causal relationship to human disease, DNA methylation is the most characterized modification. The enzymatic addition of a methyl group to DNA is performed by DNA methyltransferase (DNMT) on the 5’-carbon of the pyrimidine ring in cytosine. Four human DNMTs have been characterized: DNMT1 (Bestor et al. 1988), DNMT2 (Yoder and Bestor 1998), DNMT3a and DNMT3b (Okano et al. 1999). De novo DNA methylation patterns are established early in development by DNMT3a and DNMT3b and maintained by DNMT1, which prefers to methylate hemi-methylated templates during DNA replication through its recruitment by proliferating cell nuclear antigen (PCNA). About 3% of cytosines are methylated in the human genome almost exclusively in the context of the dinucleotide, CpG. 5-methylcytosine (5-mC) is also found in very low abundance at the trinucleotide, CpNpG (Clark et al. 1995).

CpG dinucleotides are rarer than expected in the human genome (~1%) (Josse et al. 1961; Swartz et al. 1962) as a result of 5-mC deamination and subsequent mutation to thymine (Scarano et al. 1967). 70 to 80% of CpG dinucleotides are methylated and those dinucleotides that are unmethylated tend to cluster in islands (Ehrlich et al. 1982). Regions containing the normal expected density of CpG dinucleotides are called CpG islands (CGI), which are regions no smaller than 200 bp that contain a GC content of more than 55% and an expected GC content to observed GC content ratio greater than 0.65 (Takai and Jones 2002).

Approximately 60% of human gene promoters and first exons are associated with CGIs. CGIs at promoters are frequently hypomethylated corresponding to a permissive chromatin structure in order to poise genes for a transcriptional activation (Larsen et al. 1992; Antequera and Bird 1993) while some are hypermethylated during development, which stably silences the promoter (Figure 1.1a) (Straussman et al. 2009). Such programmed CGI methylation is important for genomic imprinting, which results in monoallelic expression through the silencing of a parental allele (Kacem and Feil 2009) and gene dosage compensation such as X-chromosome inactivation in females (Reik and Lewis 2005). Recently, Doi et al. has shown that limited gene expression in differing tissue types is caused by differential methylation of CpG island shores (2009), which are located within 2.0 kb of CGIs (Figure 1.1b) (Saxonov et al. 2006). Still, a fraction of CGIs are prone to methylation in some tissues due to aging, in promoters of tumor suppressor genes in cancer cells (Issa et al. 2000), and committed cell lines (Jones et al. 1990). The remaining 40% of CGIs are located intra- and intergenically. Intragenically located CGIs within the coding region of genes are methylated at trinucleotides CpXpG (Lister et al. 2009) and are commonly found in highly expressed, constitutively active genes (Figure 1.1c) (Zhang et al. 2006) while intergenic CGIs may be used for transcription of non-coding RNAs (Illingworth et al. 2008).

Figure 1.1

Various sites and effects of DNA methylation throughout the genome

DNA methylation is found at inter- and intragenic regions throughout the genome. DNA methylation dependent transcriptional activity is contingent on CpG dinucleotide genic location and density. Normal methylation events and subsequent effects are shown on the left. (a) CpG islands at promoters are normally unmethylated resulting in gene expression. However, aberrant hypermethylation at the same promoter results in corepressor complex recruitment and subsequent gene repression. (b) Intragenic regions characterized by scattered CpG dinucleotides located 2kb upstream of the promoter called CpG island shores are regulated in the same manner as (a). (c) DNA methylation within the gene body prevents initiation of transcription from spurious sites in the gene. If unmethylated, these sites become transcriptional start sites resulting in an incorrect product. (Portela and Estellar 2010)

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Which statements about the modification of chromatin structure in eukaryotes are true?

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Some forms of chromatin modification can be passed on to future generations of cells; methylation of histone tails in chromatin can promote condensation of the chromatin; DNA is not transcribed when chromatin is packages tightly in a condensed form; acetylation of histone tails is a reversible process; acetylation of histone tails in chromatin allows access to DNA for transcription.