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Article ; Online: Epigenetic Changes and Chromatin Reorganization in Brain Function: Lessons from Fear Memory Ensemble and Alzheimer's Disease.

van Zundert, Brigitte / Montecino, Martin

International journal of molecular sciences

2022 Volume 23, Issue 20

Abstract: Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the last three decades demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components ... ...

Abstract	Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the last three decades demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components during the control of gene transcription in neural cells. Recent genome-wide analyses show that the regulation of brain genes requires the contribution of both promoter and long-distance enhancer elements, which must functionally interact with upregulated gene expression in response to physiological cues. Hence, a deep comprehension of the mechanisms mediating these enhancer-promoter interactions (EPIs) is critical if we are to understand the processes associated with learning, memory and recall. Moreover, the onset and progression of several neurodegenerative diseases and neurological alterations are found to be strongly associated with changes in the components that support and/or modulate the dynamics of these EPIs. Here, we overview relevant discoveries in the field supporting the role of the chromatin organization and of specific epigenetic mechanisms during the control of gene transcription in neural cells from healthy mice subjected to the fear conditioning paradigm, a relevant model to study memory ensemble. Additionally, special consideration is dedicated to revising recent results generated by investigators working with animal models and human postmortem brain tissue to address how changes in the epigenome and chromatin architecture contribute to transcriptional dysregulation in Alzheimer's disease, a widely studied neurodegenerative disease. We also discuss recent developments of potential new therapeutic strategies involving epigenetic editing and small chromatin-modifying molecules (or epidrugs).
MeSH term(s)	Animals ; Humans ; Mice ; Chromatin/genetics ; Alzheimer Disease/genetics ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/therapy ; Genome-Wide Association Study ; Epigenesis, Genetic ; Fear ; Brain ; Mammals/genetics
Chemical Substances	Chromatin
Language	English
Publishing date	2022-10-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232012081
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Article ; Online: Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD.

Garcés, Polett / Amaro, Armando / Montecino, Martin / van Zundert, Brigitte

Biochemical Society transactions

2024 Volume 52, Issue 1, Page(s) 123–135

Abstract: Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. ...

Abstract	Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. Despite its structural simplicity, polyP has been shown to play important roles in a remarkably broad spectrum of biological processes, including blood coagulation, bone mineralization and inflammation. Furthermore, polyP has been implicated in brain function and the neurodegenerative diseases amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease and Parkinson's disease. In this review, we first address the challenges associated with identifying mammalian polyP metabolizing enzymes, such as Nudt3, and quantifying polyP levels in brain tissue, cultured neural cells and cerebrospinal fluid. Subsequently, we focus on recent studies that unveil how the excessive release of polyP by human and mouse ALS/FTD astrocytes contributes to these devastating diseases by inducing hyperexcitability, leading to motoneuron death. Potential implications of elevated polyP levels in ALS/FTD patients for innovative diagnostic and therapeutic approaches are explored. It is emphasized, however, that caution is required in targeting polyP in the brain due to its diverse physiological functions, serving as an energy source, a chelator for divalent cations and a scaffold for amyloidogenic proteins. Reducing polyP levels, especially in neurons, might thus have adverse effects in brain functioning. Finally, we discuss how activated mast cells and platelets also can significantly contribute to ALS progression, as they can massively release polyP.
MeSH term(s)	Animals ; Mice ; Humans ; Frontotemporal Dementia/metabolism ; Frontotemporal Dementia/therapy ; Amyotrophic Lateral Sclerosis/diagnosis ; Amyotrophic Lateral Sclerosis/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism ; Polyphosphates ; Alzheimer Disease ; Parkinson Disease ; Mammals
Chemical Substances	Polyphosphates
Language	English
Publishing date	2024-02-07
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20230257
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Article: Epigenetic regulation during 1,25-dihydroxyvitamin D

Moena, Daniel / Vargas, Esther / Montecino, Martin

Vitamins and hormones

2023 Volume 122, Page(s) 51–74

Abstract: Multiple evidence accumulated over the years, demonstrates that vitamin D-dependent physiological control in vertebrates occurs primarily through the regulation of target gene transcription. In addition, there has been an increasing appreciation of the ... ...

Abstract	Multiple evidence accumulated over the years, demonstrates that vitamin D-dependent physiological control in vertebrates occurs primarily through the regulation of target gene transcription. In addition, there has been an increasing appreciation of the role of the chromatin organization of the genome on the ability of the active form of vitamin D, 1,25(OH)
MeSH term(s)	Humans ; Animals ; Epigenesis, Genetic ; Vitamin D/pharmacology ; Vitamins ; Chromatin/genetics ; Transcription, Genetic ; Mammals
Chemical Substances	1,25-dihydroxyvitamin D (66772-14-3) ; Vitamin D (1406-16-2) ; Vitamins ; Chromatin
Language	English
Publishing date	2023-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/bs.vh.2023.01.005
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Article: Epigenetic Control of Osteogenic Lineage Commitment.

Montecino, Martin / Carrasco, Margarita E / Nardocci, Gino

Frontiers in cell and developmental biology

2021 Volume 8, Page(s) 611197

Abstract: Within the eukaryotic nucleus the genomic DNA is organized into chromatin by stably interacting with the histone proteins as well as with several other nuclear components including non-histone proteins and non-coding RNAs. Together these interactions ... ...

Abstract	Within the eukaryotic nucleus the genomic DNA is organized into chromatin by stably interacting with the histone proteins as well as with several other nuclear components including non-histone proteins and non-coding RNAs. Together these interactions distribute the genetic material into chromatin subdomains which can exhibit higher and lower compaction levels. This organization contributes to differentially control the access to genomic sequences encoding key regulatory genetic information. In this context, epigenetic mechanisms play a critical role in the regulation of gene expression as they modify the degree of chromatin compaction to facilitate both activation and repression of transcription. Among the most studied epigenetic mechanisms we find the methylation of DNA, ATP-dependent chromatin remodeling, and enzyme-mediated deposition and elimination of post-translational modifications at histone and non-histone proteins. In this mini review, we discuss evidence that supports the role of these epigenetic mechanisms during transcriptional control of osteoblast-related genes. Special attention is dedicated to mechanisms of epigenetic control operating at the Runx2 and Sp7 genes coding for the two principal master regulators of the osteogenic lineage during mesenchymal stem cell commitment.
Language	English
Publishing date	2021-01-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2020.611197
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Article ; Online: Long Noncoding RNA TALAM1 Is a Transcriptional Target of the RUNX2 Transcription Factor in Lung Adenocarcinoma.

Bermúdez, Gisella / Bernal, Camila / Otalora, Andrea / Sanchez, Paula / Nardocci, Gino / Cañas, Alejandra / Lopez-Kleine, Liliana / Montecino, Martín / Rojas, Adriana

Current issues in molecular biology

2023 Volume 45, Issue 9, Page(s) 7075–7086

Abstract: Background: Lung cancer is the leading cause of cancer death worldwide. It has been reported that genetic and epigenetic factors play a crucial role in the onset and evolution of lung cancer. Previous reports have shown that essential transcription ... ...

Abstract	Background: Lung cancer is the leading cause of cancer death worldwide. It has been reported that genetic and epigenetic factors play a crucial role in the onset and evolution of lung cancer. Previous reports have shown that essential transcription factors in embryonic development contribute to this pathology. Runt-related transcription factor (RUNX) proteins belong to a family of master regulators of embryonic developmental programs. Specifically, RUNX2 is the master transcription factor (TF) of osteoblastic differentiation, and it can be involved in pathological conditions such as prostate, thyroid, and lung cancer by regulating apoptosis and mesenchymal-epithelial transition processes. In this paper, we identified Methods: We performed ChIP-seq analysis of tumor samples from a patient diagnosed with lung adenocarcinoma to evaluate the target genes of the RUNX2 TF. In addition, we performed shRNA-mediated knockdown of RUNX2 in this lung adenocarcinoma cell line to confirm the regulatory role of RUNX2 in Results: We observed RUNX2 overexpression in cell lines and primary cultured lung cancer cells. Interestingly, we found that lncRNA TALAM1 was a target of RUNX2 and that RUNX2 exerted a negative regulatory effect on
Language	English
Publishing date	2023-08-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2000024-8
ISSN	1467-3045 ; 1467-3037
ISSN (online)	1467-3045
ISSN	1467-3037
DOI	10.3390/cimb45090447
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Article ; Online: Epigenetic Control of Osteogenic Lineage Commitment

Martin Montecino / Margarita E. Carrasco / Gino Nardocci

Frontiers in Cell and Developmental Biology, Vol

2021 Volume 8

Abstract	Within the eukaryotic nucleus the genomic DNA is organized into chromatin by stably interacting with the histone proteins as well as with several other nuclear components including non-histone proteins and non-coding RNAs. Together these interactions distribute the genetic material into chromatin subdomains which can exhibit higher and lower compaction levels. This organization contributes to differentially control the access to genomic sequences encoding key regulatory genetic information. In this context, epigenetic mechanisms play a critical role in the regulation of gene expression as they modify the degree of chromatin compaction to facilitate both activation and repression of transcription. Among the most studied epigenetic mechanisms we find the methylation of DNA, ATP-dependent chromatin remodeling, and enzyme-mediated deposition and elimination of post-translational modifications at histone and non-histone proteins. In this mini review, we discuss evidence that supports the role of these epigenetic mechanisms during transcriptional control of osteoblast-related genes. Special attention is dedicated to mechanisms of epigenetic control operating at the Runx2 and Sp7 genes coding for the two principal master regulators of the osteogenic lineage during mesenchymal stem cell commitment.
Keywords	epigenetic control ; bone-related expression ; osteoblast differentiation ; histone marks ; chromatin ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Selective Concurrence of the Long Non-Coding RNA MALAT1 and the Polycomb Repressive Complex 2 to Promoter Regions of Active Genes in MCF7 Breast Cancer Cells.

Arratia, Felipe / Fierro, Cristopher / Blanco, Alejandro / Fuentes, Sebastian / Nahuelquen, Daniela / Montecino, Martin / Rojas, Adriana / Aguilar, Rodrigo

Current issues in molecular biology

2023 Volume 45, Issue 6, Page(s) 4735–4748

Abstract: In cancer cells, the long non-coding RNA (lncRNA) MALAT1 has arisen as a key partner for the Polycomb Repressive Complex 2 (PRC2), an epigenetic modifier. However, it is unknown whether this partnership occurs genome-wide at the chromatin level, as most ... ...

Abstract	In cancer cells, the long non-coding RNA (lncRNA) MALAT1 has arisen as a key partner for the Polycomb Repressive Complex 2 (PRC2), an epigenetic modifier. However, it is unknown whether this partnership occurs genome-wide at the chromatin level, as most of the studies focus on single genes that are usually repressed. Due to the genomic binding properties of both macromolecules, we wondered whether there are binding sites shared by PRC2 and MALAT1. Using public genome-binding datasets for PRC2 and MALAT1 derived from independent ChIP- and CHART-seq experiments performed with the breast cancer cell line MCF7, we searched for regions containing PRC2 and MALAT1 overlapping peaks. Peak calls for each molecule were performed using MACS2 and then overlapping peaks were identified by bedtools intersect. Using this approach, we identified 1293 genomic sites where PRC2 and MALAT1 concur. Interestingly, 54.75% of those sites are within gene promoter regions (<3000 bases from the TSS). These analyses were also linked with the transcription profiles of MCF7 cells, obtained from public RNA-seq data. Hence, it is suggested that MALAT1 and PRC2 can concomitantly bind to promoters of actively-transcribed genes in MCF7 cells. Gene ontology analyses revealed an enrichment of genes related to categories including cancer malignancy and epigenetic regulation. Thus, by re-visiting occupancy and transcriptomic data, we identified a key gene subset controlled by the collaboration of MALAT1 and PRC2.
Language	English
Publishing date	2023-05-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2000024-8
ISSN	1467-3045 ; 1467-3037
ISSN (online)	1467-3045
ISSN	1467-3037
DOI	10.3390/cimb45060301
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Article ; Online: Evidence supporting that human-subsidized free-ranging dogs are the main cause of animal losses in small-scale farms in Chile.

Montecino-Latorre, Diego / San Martín, William

Ambio

2018 Volume 48, Issue 3, Page(s) 240–250

Abstract: We surveyed professionals from the Chilean Ministry of Agriculture working with small-scale farmers to characterize the attacks of free-ranging dogs across Chile. Nationwide, in a single year, free-ranging dogs attacked 25% of the ca. 8500 farms included ...

Abstract	We surveyed professionals from the Chilean Ministry of Agriculture working with small-scale farmers to characterize the attacks of free-ranging dogs across Chile. Nationwide, in a single year, free-ranging dogs attacked 25% of the ca. 8500 farms included in the survey, killing or injuring about 10 000 small ruminants. These dogs were ranked as the main cause of animal losses for small-scale farmers, representing a threat to the livelihoods of this vulnerable group. Further, free-ranging dogs attacking small ruminants were considered as human-subsidized, since they would be recruited by irresponsible ownership and abandonment from urban centers. This is the first national assessment reporting that human-subsidized dogs are a main threat to livestock rearing. Policies to control populations of these animals should target their anthropogenic origin as well as cultural shifts in dog ownership and animal welfare. While these policies may be effective mid- to long-term approaches, short-term actions may also be needed.
MeSH term(s)	Animal Welfare ; Animals ; Chile ; Dogs ; Farms ; Humans ; Livestock ; Ownership
Language	English
Publishing date	2018-06-15
Publishing country	Sweden
Document type	Journal Article
ZDB-ID	120759-3
ISSN	1654-7209 ; 0044-7447
ISSN (online)	1654-7209
ISSN	0044-7447
DOI	10.1007/s13280-018-1066-3
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Article: Evidence supporting that human-subsidized free-ranging dogs are the main cause of animal losses in small-scale farms in Chile

Montecino-Latorre, Diego / San Martín, William

Ambio. 2019 Mar., v. 48, no. 3

2019

Abstract	We surveyed professionals from the Chilean Ministry of Agriculture working with small-scale farmers to characterize the attacks of free-ranging dogs across Chile. Nationwide, in a single year, free-ranging dogs attacked 25% of the ca. 8500 farms included in the survey, killing or injuring about 10 000 small ruminants. These dogs were ranked as the main cause of animal losses for small-scale farmers, representing a threat to the livelihoods of this vulnerable group. Further, free-ranging dogs attacking small ruminants were considered as human-subsidized, since they would be recruited by irresponsible ownership and abandonment from urban centers. This is the first national assessment reporting that human-subsidized dogs are a main threat to livestock rearing. Policies to control populations of these animals should target their anthropogenic origin as well as cultural shifts in dog ownership and animal welfare. While these policies may be effective mid- to long-term approaches, short-term actions may also be needed.
Keywords	animal welfare ; dogs ; farmers ; issues and policy ; livelihood ; ownership ; professionals ; rearing ; small farms ; small ruminants ; surveys ; Chile
Language	English
Dates of publication	2019-03
Size	p. 240-250.
Publishing place	Springer Netherlands
Document type	Article
ZDB-ID	120759-3
ISSN	1654-7209 ; 0044-7447
ISSN (online)	1654-7209
ISSN	0044-7447
DOI	10.1007/s13280-018-1066-3
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Article ; Online: Epigenetic regulators controlling osteogenic lineage commitment and bone formation.

Dashti, Parisa / Lewallen, Eric A / Gordon, Jonathan A R / Montecino, Martin A / Davie, James R / Stein, Gary S / van Leeuwen, Johannes P T M / van der Eerden, Bram C J / van Wijnen, Andre J

Bone

2024 Volume 181, Page(s) 117043

Abstract: Bone formation and homeostasis are controlled by environmental factors and endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating gene expression in the nucleus. Bone-related gene expression is controlled by ... ...

Abstract	Bone formation and homeostasis are controlled by environmental factors and endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating gene expression in the nucleus. Bone-related gene expression is controlled by nucleosome-based chromatin architecture that limits the accessibility of lineage-specific gene regulatory DNA sequences and sequence-specific transcription factors. From a developmental perspective, bone-specific gene expression must be suppressed during the early stages of embryogenesis to prevent the premature mineralization of skeletal elements during fetal growth in utero. Hence, bone formation is initially inhibited by gene suppressive epigenetic regulators, while other epigenetic regulators actively support osteoblast differentiation. Prominent epigenetic regulators that stimulate or attenuate osteogenesis include lysine methyl transferases (e.g., EZH2, SMYD2, SUV420H2), lysine deacetylases (e.g., HDAC1, HDAC3, HDAC4, HDAC7, SIRT1, SIRT3), arginine methyl transferases (e.g., PRMT1, PRMT4/CARM1, PRMT5), dioxygenases (e.g., TET2), bromodomain proteins (e.g., BRD2, BRD4) and chromodomain proteins (e.g., CBX1, CBX2, CBX5). This narrative review provides a broad overview of the covalent modifications of DNA and histone proteins that involve hundreds of enzymes that add, read, or delete these epigenetic modifications that are relevant for self-renewal and differentiation of mesenchymal stem cells, skeletal stem cells and osteoblasts during osteogenesis.
MeSH term(s)	Osteogenesis/genetics ; Transcription Factors/metabolism ; Lysine/metabolism ; Nuclear Proteins/genetics ; Cell Differentiation/genetics ; Epigenesis, Genetic ; Osteoblasts/metabolism ; Transferases/genetics ; Transferases/metabolism
Chemical Substances	Transcription Factors ; Lysine (K3Z4F929H6) ; Nuclear Proteins ; Transferases (EC 2.-)
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	632515-4
ISSN	1873-2763 ; 8756-3282
ISSN (online)	1873-2763
ISSN	8756-3282
DOI	10.1016/j.bone.2024.117043
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