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Linking epigenetics to human disease and Rett syndrome: the emerging novel and challenging concepts in MeCP2 research.

Zachariah RM, Rastegar M - Neural Plast. (2012)

Bottom Line: Despite the fact that MeCP2 was discovered about 20 years ago, our current knowledge about its molecular function is not comprehensive.While MeCP2 was originally found to bind methylated DNA and interact with repressor complexes to inhibit and silence its genomic targets, recent studies have challenged this idea.Indeed, depending on its interacting protein partners and target genes, MeCP2 can act either as an activator or as a repressor.

View Article: PubMed Central - PubMed

Affiliation: Regenerative Medicine Program, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada.

ABSTRACT
Epigenetics refer to inheritable changes beyond DNA sequence that control cell identity and morphology. Epigenetics play key roles in development and cell fate commitments and highly impact the etiology of many human diseases. A well-known link between epigenetics and human disease is the X-linked MECP2 gene, mutations in which lead to the neurological disorder, Rett Syndrome. Despite the fact that MeCP2 was discovered about 20 years ago, our current knowledge about its molecular function is not comprehensive. While MeCP2 was originally found to bind methylated DNA and interact with repressor complexes to inhibit and silence its genomic targets, recent studies have challenged this idea. Indeed, depending on its interacting protein partners and target genes, MeCP2 can act either as an activator or as a repressor. Furthermore, it is becoming evident that although Rett Syndrome is a progressive and postnatal neurological disorder, the consequences of MeCP2 deficiencies initiate much earlier and before birth. To comprehend the novel and challenging concepts in MeCP2 research and to design effective therapeutic strategies for Rett Syndrome, a targeted collaborative effort from scientists in multiple research areas to clinicians is required.

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Related in: MedlinePlus

MECP2 gene and protein isoforms. Schematic illustration of the gene structure of MECP2 and the different domains of the two protein isoforms, MeCP2E1 and MeCP2E2. The primary amino acid composition of the N-terminus of MeCP2E1 and MeCP2E2 is depicted.
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fig2: MECP2 gene and protein isoforms. Schematic illustration of the gene structure of MECP2 and the different domains of the two protein isoforms, MeCP2E1 and MeCP2E2. The primary amino acid composition of the N-terminus of MeCP2E1 and MeCP2E2 is depicted.

Mentions: The MECP2 gene maps between L1CAM and the RCP/GCP loci in Xq28 and undergoes X-Chromosome Inactivation (XCI) in females [24, 25]. The genomic locus of MECP2 spans approximately 76 kb and consists of four exons encoding two different isoforms (MeCP2E1 and MeCP2E2), due to alternate splicing of exon 2 (Figure 2). The more abundant E1 isoform contains 24 amino acids encoded by exon 1 and lacks the 9 amino acids encoded by exon 2, whereas the start site for the E2 lies within the exon 2 [26]. Of the two isoforms, MECP2E1 is more efficiently translated and show 10X more expression than MECP2E2 in brain. Mecp2 has a large, highly conserved 3′UTR that contains multiple polyadenylation sites. Alternative 3′UTR usage leads to three distinct transcripts, short 1.8 kb and long 10 kb transcripts, with the latter including a highly conserved (8.5 kb) 3′UTR, and a third additional low abundance transcript of approximately 5–7 kb [27]. MeCP2 is a nuclear protein that is mainly colocalized with densely methylated heterochromatin in mouse cells. The differential expression of Mecp2/MECP2 transcripts can be subjected to tissue- and developmental stage-specific regulation. In the brain, differential transcript expression patterns for the two isoforms have been detected [28]. The transcript levels are high during embryogenesis with a postnatal decrease, but increasing again towards adulthood. On the other hand, the protein levels are low during embryogenesis and increase postnatally upon neuronal maturation [29].


Linking epigenetics to human disease and Rett syndrome: the emerging novel and challenging concepts in MeCP2 research.

Zachariah RM, Rastegar M - Neural Plast. (2012)

MECP2 gene and protein isoforms. Schematic illustration of the gene structure of MECP2 and the different domains of the two protein isoforms, MeCP2E1 and MeCP2E2. The primary amino acid composition of the N-terminus of MeCP2E1 and MeCP2E2 is depicted.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3306986&req=5

fig2: MECP2 gene and protein isoforms. Schematic illustration of the gene structure of MECP2 and the different domains of the two protein isoforms, MeCP2E1 and MeCP2E2. The primary amino acid composition of the N-terminus of MeCP2E1 and MeCP2E2 is depicted.
Mentions: The MECP2 gene maps between L1CAM and the RCP/GCP loci in Xq28 and undergoes X-Chromosome Inactivation (XCI) in females [24, 25]. The genomic locus of MECP2 spans approximately 76 kb and consists of four exons encoding two different isoforms (MeCP2E1 and MeCP2E2), due to alternate splicing of exon 2 (Figure 2). The more abundant E1 isoform contains 24 amino acids encoded by exon 1 and lacks the 9 amino acids encoded by exon 2, whereas the start site for the E2 lies within the exon 2 [26]. Of the two isoforms, MECP2E1 is more efficiently translated and show 10X more expression than MECP2E2 in brain. Mecp2 has a large, highly conserved 3′UTR that contains multiple polyadenylation sites. Alternative 3′UTR usage leads to three distinct transcripts, short 1.8 kb and long 10 kb transcripts, with the latter including a highly conserved (8.5 kb) 3′UTR, and a third additional low abundance transcript of approximately 5–7 kb [27]. MeCP2 is a nuclear protein that is mainly colocalized with densely methylated heterochromatin in mouse cells. The differential expression of Mecp2/MECP2 transcripts can be subjected to tissue- and developmental stage-specific regulation. In the brain, differential transcript expression patterns for the two isoforms have been detected [28]. The transcript levels are high during embryogenesis with a postnatal decrease, but increasing again towards adulthood. On the other hand, the protein levels are low during embryogenesis and increase postnatally upon neuronal maturation [29].

Bottom Line: Despite the fact that MeCP2 was discovered about 20 years ago, our current knowledge about its molecular function is not comprehensive.While MeCP2 was originally found to bind methylated DNA and interact with repressor complexes to inhibit and silence its genomic targets, recent studies have challenged this idea.Indeed, depending on its interacting protein partners and target genes, MeCP2 can act either as an activator or as a repressor.

View Article: PubMed Central - PubMed

Affiliation: Regenerative Medicine Program, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada.

ABSTRACT
Epigenetics refer to inheritable changes beyond DNA sequence that control cell identity and morphology. Epigenetics play key roles in development and cell fate commitments and highly impact the etiology of many human diseases. A well-known link between epigenetics and human disease is the X-linked MECP2 gene, mutations in which lead to the neurological disorder, Rett Syndrome. Despite the fact that MeCP2 was discovered about 20 years ago, our current knowledge about its molecular function is not comprehensive. While MeCP2 was originally found to bind methylated DNA and interact with repressor complexes to inhibit and silence its genomic targets, recent studies have challenged this idea. Indeed, depending on its interacting protein partners and target genes, MeCP2 can act either as an activator or as a repressor. Furthermore, it is becoming evident that although Rett Syndrome is a progressive and postnatal neurological disorder, the consequences of MeCP2 deficiencies initiate much earlier and before birth. To comprehend the novel and challenging concepts in MeCP2 research and to design effective therapeutic strategies for Rett Syndrome, a targeted collaborative effort from scientists in multiple research areas to clinicians is required.

Show MeSH
Related in: MedlinePlus