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Epigenetics and Chromatin

, 7:37

First Online: 09 December 2014Received: 29 October 2014Accepted: 28 November 2014

Abstract

In 1984 Sir Francis Crick hypothesized that memory is recorded in the brain as reversible modifications to DNA and protein, but acknowledged that most biomolecules turn over too rapidly to account for long-term memories. To accommodate this possible paradox he modeled an enzymatic mechanism to maintain modifications on hemi-modified multimeric symmetrical molecules. While studies on the turnover of chromatin modifications that may be involved in memory are in their infancy, an exploration of his model in the light of modern epigenetics produced somewhat surprising results. The molecular turnover rates for two classes of chromatin modifications believed to record and store durable memories were approximated from experiments using diverse approaches and were found to be remarkably short. The half-lives of DNA cytosine methylation and post-translationally modified nucleosomal histones are measured in hours and minutes, respectively, for a subset of sites on chromatin controlling gene expression. It appears likely that the turnover of DNA methylation in the brain and in neurons, in particular, is even more rapid than in other cell types and organs, perhaps accommodating neuronal plasticity, learning, and memory. The machinery responsible for the rapid turnover of DNA methylation and nucleosomal histone modifications is highly complex, partially redundant, and appears to act in a sequence specific manner. Molecular symmetry plays an important part in maintaining site-specific turnover, but its particular role in memory maintenance is unknown. Elucidating Crick’s paradox, the contradiction between rapid molecular turnover of modified biomolecules and long-term memory storage, appears fundamental to understanding cognitive function and neurodegenerative disease.

KeywordsMethylcytosine Hydroxymethylcytosine Post-translational modification Histones Acetylation Nucleosomes General abbreviationsAzaC5-aza-2′-deoxycytidine

Ahaazidohomoalanine

bpbase pair

BERbase excision repair

CDIchromatin domain inheritance

CGICG rich Islands

CNScentral nervous system

ECTElectroconvulsive treatment

ES cellsembryonic stem cells

HEK293T cellshuman embryonic kidney 293 cells

histone PTMhistone post-translational modification

INTACTisolation of nuclei tagged in specific cell types 63, 64

NPCneural progenitor cell

C5′-methylcytosine

C5′-hydroxymethylcytosine

C5′-formylcytosine

C5′-carboxylcytosine

RNAiRNA interference

TDGthymine-DNA glycosylase

Protein-gene abbreviationsAid-AICDAActivation-Induced Cytidine Deaminase

Aprtadenine phosphoribosyltransferase

APC-PPP1R46Adenomatous Polyposis Coli

ARCActivity-regulated cytoskeleton-associated protein

ASF1histone chaperone anti-silencing factor 1

BDNFBrain-derived neurotrophic factor

BRE-BRACC45Brain And Reproductive Organ-Expressed

BRN2- POU3F2Brain-specific 2-N gene POU domain class 3 homeobox 2

CENH3centromeric histone 3

CRTC1CREB-regulated transcriptional coactivator

CRYAA-CRYA1Crystallin, Alpha A

DAZ1-SPGYDeleted In Azoospermia 1

DNMTsDNA methyltransferases 1, 3A, 3B from mammals and 1 4, 5, 7 from fish

DRM1, DRM2, CMT3RNA directed de novo DNA methyltransferases

FGF-B1-FGF2Fibroblast growth factor 1 basic

FosFBJ Murine Osteosarcoma Viral Oncogene Homolog

GADD45a, GADD45β and GADD45gDNA cytosine demethylases Growth arrest DNA damage inducible protein isoforms

HDAChistone deacetylase

H2AZhistone 2a, isoform Z

Mbd4-MED1Methyl-CpG Binding Domain Protein 4

MeCP2methyl-CpG binding protein 2

MKK7mitogen-activated protein kinase kinase 7

MYD118myeloid differentiation primary response factor

microRNA 124miR-124

Npas4Neuronal PAS Domain Protein 4

NeuN-RBFOX3Neuronal nuclei, Hexaribonucleotide Binding Protein 3

OCT4-POU5F1Octamer-binding transcription factor 4, PKMζ protein kinase M zeta, POU domain, class 5, transcription factor 1

PP1C-PP1Cγ-PPP1Gserine threonine protein phosphatase 1, gamma subunit

pS2-BEC1Breast Cancer Estrogen-Inducible Protein, Trefoil Factor 1

RELNReelin

SV40simian vacuolating virus 40

TET1, 2, 3ten-eleven-translocation DNA dioxygenases

TK1Thymidine kinase 1

TOP1Topoisomerase DNA 1

XbraXenopus brachyury

Electronic supplementary materialThe online version of this article doi:10.1186-1756-8935-7-37 contains supplementary material, which is available to authorized users.

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Author: Richard B Meagher

Source: https://link.springer.com/



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