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The long-term impact of adverse caregiving environments on epigenetic modifications and telomeres.

Blaze J, Asok A, Roth TL - Front Behav Neurosci (2015)

Bottom Line: Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior.Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health.This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychological and Brain Sciences, University of Delaware Newark, DE, USA.

ABSTRACT
Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior. Clinical studies have demonstrated that infants who experience stress and adversity in the context of caregiving are at an increased risk for the development of psychiatric disorders. Animal models have helped to elucidate some molecular substrates of these risk factors, but a complete picture of the biological basis remains unknown. Studies continue to indicate that environmentally-driven epigenetic modifications may be an important mediator between adverse caregiving environments and psychopathology. Epigenetic modifications such as DNA methylation, which normally represses gene transcription, and microRNA processing, which interferes with both transcription and translation, show long-term changes throughout the brain and body following adverse caregiving. Recent evidence has also shown that telomeres (TTAGGG nucleotide repeats that cap the ends of DNA) exhibit long-term changes in the brain and in the periphery following exposure to adverse caregiving environments. Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health. This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.

No MeSH data available.


Related in: MedlinePlus

Telomeres are regulated by telomeric-specific proteins and are subject to epigenetic regulation. (A) Telomeres are TTAGGG nucleotide repeats that (A1) contain a subtelomeric region and telomeric region that surrounds chromatin, in addition to (A2) a 50–300 bp overhang on the 3’ strand of DNA. (A2) Stress can induce shortening of telomeres whereas telomerase promotes elongation. (B) Telomere length is regulated by proteins within the (B1) shelterin and telomerase complexes. Shelterin proteins have a crucial role in recruiting and positioning (B2) telomerase RNA (TR) and telomerase reverse transcriptase (TERT) on the ends of telomeres during maintenance and repair. (C) In their native state, (C1) telomeres are in a hypermethylated state that is regulated and maintained by key DNA methyltransferases including DNMT1, DNA methyltransferase 3a (DNMT3a), and DNMT3b. However, (C2) telomere shortening induces a shift to a euchromatic state involving increased acetylation and decreased methylation which (C3) facilitates the recruitment of telomerase to telomere ends. Abbreviations: TTAGGG-repeat binding factor 1 (TRF1), TTAGGG-repeat binding factor 2 (TRF2), collective acronym of previous labels TINT1, PTOP, and PIP1 (TPP1), TRF-1 interacting nuclear protein/factor 2 (TIN2), (RAP1), protection of telomeres 1 (POT1), telomerase reverse transcriptase (TERT), TR, methyl group (pentagonal M), acetyl group (pentagonal A).
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Figure 2: Telomeres are regulated by telomeric-specific proteins and are subject to epigenetic regulation. (A) Telomeres are TTAGGG nucleotide repeats that (A1) contain a subtelomeric region and telomeric region that surrounds chromatin, in addition to (A2) a 50–300 bp overhang on the 3’ strand of DNA. (A2) Stress can induce shortening of telomeres whereas telomerase promotes elongation. (B) Telomere length is regulated by proteins within the (B1) shelterin and telomerase complexes. Shelterin proteins have a crucial role in recruiting and positioning (B2) telomerase RNA (TR) and telomerase reverse transcriptase (TERT) on the ends of telomeres during maintenance and repair. (C) In their native state, (C1) telomeres are in a hypermethylated state that is regulated and maintained by key DNA methyltransferases including DNMT1, DNA methyltransferase 3a (DNMT3a), and DNMT3b. However, (C2) telomere shortening induces a shift to a euchromatic state involving increased acetylation and decreased methylation which (C3) facilitates the recruitment of telomerase to telomere ends. Abbreviations: TTAGGG-repeat binding factor 1 (TRF1), TTAGGG-repeat binding factor 2 (TRF2), collective acronym of previous labels TINT1, PTOP, and PIP1 (TPP1), TRF-1 interacting nuclear protein/factor 2 (TIN2), (RAP1), protection of telomeres 1 (POT1), telomerase reverse transcriptase (TERT), TR, methyl group (pentagonal M), acetyl group (pentagonal A).

Mentions: Another biomarker for measuring the impact of early-life stress is telomere length, which is also subject to epigenetic modifications. Telomeres are long stretches of TTAGGG nucleotide repeats located at the ends of chromosomes that function to protect genomic DNA from damage following replication. They are primarily double stranded except near the terminal ends where there is a 50–300 base pair overhang of the 3’ TTAGGG strand (Figure 2A). With each cell-division, telomeres naturally shorten in length (i.e., the “end replication problem” (Blackburn, 1991) before reaching a critical point which triggers replicative senescence. Given that telomeres continually shorten with each cell division throughout the lifespan, the length of telomeres has been proposed as a measure of disease-risk (e.g., cardiovascular disease) and biological aging. However, studies investigating its utility as a measure for biological aging have been discrepant (von Zglinicki and Martin-Ruiz, 2005; Mather et al., 2011; Fossel, 2012).


The long-term impact of adverse caregiving environments on epigenetic modifications and telomeres.

Blaze J, Asok A, Roth TL - Front Behav Neurosci (2015)

Telomeres are regulated by telomeric-specific proteins and are subject to epigenetic regulation. (A) Telomeres are TTAGGG nucleotide repeats that (A1) contain a subtelomeric region and telomeric region that surrounds chromatin, in addition to (A2) a 50–300 bp overhang on the 3’ strand of DNA. (A2) Stress can induce shortening of telomeres whereas telomerase promotes elongation. (B) Telomere length is regulated by proteins within the (B1) shelterin and telomerase complexes. Shelterin proteins have a crucial role in recruiting and positioning (B2) telomerase RNA (TR) and telomerase reverse transcriptase (TERT) on the ends of telomeres during maintenance and repair. (C) In their native state, (C1) telomeres are in a hypermethylated state that is regulated and maintained by key DNA methyltransferases including DNMT1, DNA methyltransferase 3a (DNMT3a), and DNMT3b. However, (C2) telomere shortening induces a shift to a euchromatic state involving increased acetylation and decreased methylation which (C3) facilitates the recruitment of telomerase to telomere ends. Abbreviations: TTAGGG-repeat binding factor 1 (TRF1), TTAGGG-repeat binding factor 2 (TRF2), collective acronym of previous labels TINT1, PTOP, and PIP1 (TPP1), TRF-1 interacting nuclear protein/factor 2 (TIN2), (RAP1), protection of telomeres 1 (POT1), telomerase reverse transcriptase (TERT), TR, methyl group (pentagonal M), acetyl group (pentagonal A).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4389567&req=5

Figure 2: Telomeres are regulated by telomeric-specific proteins and are subject to epigenetic regulation. (A) Telomeres are TTAGGG nucleotide repeats that (A1) contain a subtelomeric region and telomeric region that surrounds chromatin, in addition to (A2) a 50–300 bp overhang on the 3’ strand of DNA. (A2) Stress can induce shortening of telomeres whereas telomerase promotes elongation. (B) Telomere length is regulated by proteins within the (B1) shelterin and telomerase complexes. Shelterin proteins have a crucial role in recruiting and positioning (B2) telomerase RNA (TR) and telomerase reverse transcriptase (TERT) on the ends of telomeres during maintenance and repair. (C) In their native state, (C1) telomeres are in a hypermethylated state that is regulated and maintained by key DNA methyltransferases including DNMT1, DNA methyltransferase 3a (DNMT3a), and DNMT3b. However, (C2) telomere shortening induces a shift to a euchromatic state involving increased acetylation and decreased methylation which (C3) facilitates the recruitment of telomerase to telomere ends. Abbreviations: TTAGGG-repeat binding factor 1 (TRF1), TTAGGG-repeat binding factor 2 (TRF2), collective acronym of previous labels TINT1, PTOP, and PIP1 (TPP1), TRF-1 interacting nuclear protein/factor 2 (TIN2), (RAP1), protection of telomeres 1 (POT1), telomerase reverse transcriptase (TERT), TR, methyl group (pentagonal M), acetyl group (pentagonal A).
Mentions: Another biomarker for measuring the impact of early-life stress is telomere length, which is also subject to epigenetic modifications. Telomeres are long stretches of TTAGGG nucleotide repeats located at the ends of chromosomes that function to protect genomic DNA from damage following replication. They are primarily double stranded except near the terminal ends where there is a 50–300 base pair overhang of the 3’ TTAGGG strand (Figure 2A). With each cell-division, telomeres naturally shorten in length (i.e., the “end replication problem” (Blackburn, 1991) before reaching a critical point which triggers replicative senescence. Given that telomeres continually shorten with each cell division throughout the lifespan, the length of telomeres has been proposed as a measure of disease-risk (e.g., cardiovascular disease) and biological aging. However, studies investigating its utility as a measure for biological aging have been discrepant (von Zglinicki and Martin-Ruiz, 2005; Mather et al., 2011; Fossel, 2012).

Bottom Line: Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior.Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health.This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychological and Brain Sciences, University of Delaware Newark, DE, USA.

ABSTRACT
Early childhood is a sensitive period in which infant-caregiver experiences have profound effects on brain development and behavior. Clinical studies have demonstrated that infants who experience stress and adversity in the context of caregiving are at an increased risk for the development of psychiatric disorders. Animal models have helped to elucidate some molecular substrates of these risk factors, but a complete picture of the biological basis remains unknown. Studies continue to indicate that environmentally-driven epigenetic modifications may be an important mediator between adverse caregiving environments and psychopathology. Epigenetic modifications such as DNA methylation, which normally represses gene transcription, and microRNA processing, which interferes with both transcription and translation, show long-term changes throughout the brain and body following adverse caregiving. Recent evidence has also shown that telomeres (TTAGGG nucleotide repeats that cap the ends of DNA) exhibit long-term changes in the brain and in the periphery following exposure to adverse caregiving environments. Interestingly, telomeric enzymes and subtelomeric regions are subject to epigenetic modifications-a factor which may play an important role in regulating telomere length and contribute to future mental health. This review will focus on clinical and animal studies that highlight the long-term epigenetic and telomeric changes produced by adverse caregiving in early-life.

No MeSH data available.


Related in: MedlinePlus