Research Topic

Gene expression, Molecular Pathways and Organelle Alterations in Down syndrome Phenotype.

About this Research Topic

Down syndrome is the most frequent genetic condition and the first chromosomal disorder for which the cause was identified: the presence of 3 copies of all or part of chromosome 21 (Hsa21). The molecular mechanisms that underlie the phenotypic alterations, especially cognitive impairment, are not yet fully elucidated. This is not surprising in light of the severity of the genetic alteration: the presence of an extra chromosome implies that there are three copies of more than 250 genes mapping to it, with a potential gene dosage problem for each of them.



A large number of transcriptomics studies has been conducted with the aim of identifying clusters of dysregulated genes, located either on Hsa21 or on other chromosomes, which operate in the same pathways or related ones. Their alterations could shed light on the molecular basis of a particular phenotypic abnormality. Transcriptomic studies have been carried out with different methodologies and on different tissues and cells. As a consequence, resulting data have often shown limited overlap, thus producing less interesting outcome than expected. In addition, recent studies have suggested that the presence of an extra chromosome in the nucleus can determine in itself a nuclear reorganization capable of altering gene expression independently on gene dosage.



Nevertheless, numerous studies have pursued the objective of clarifying the role of single Hsa21 genes in determining specific alterations at molecular, cellular and finally at phenotypic level. The attention has been preferentially focused on the genes mapping to the so-called ‘critical region for DS’, such as the dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1 A (DYRK1A), the regulator of calcineurin 1 (RCAN1), the cystathionine beta-synthase (CBS), the superoxide dismutase 1 (SOD1) and others. However, also genes outside the critical region have demonstrated to contribute to specific alterations. This is the case of the repressor gene NRIP1, which affects the expression of nuclear encoded mitochondrial genes and mitochondrial function. One should not neglect the effects of trisomy of Hsa21 non coding regions, which harbour microRNAs, as well as long noncoding RNAs and other RNA molecules, that may modulate target genes.



The aim of this Research Topic is to focus on those approaches that shed light on the molecular bases of DS, assuming that the dysregulation of one or more genes may perturb pathways that in turn affect organelle structure and function, thus producing phenotypic effects. The starting point can be investigating a gene, a pathway or an organelle, but the next important step will be to link them together to generate a holistic view of the processes in which they are involved and their role in the syndrome traits.



We welcome the submission of original research, brief research reports, and review manuscripts focusing on the following major facets of DS studies:



- multiomic approaches, such as genomic organization, transcriptome, proteome, epigenome, methylome, metabolome, etc;

- molecular pathways, such as respiration, energy conversion, ATP synthesis, ER stress, autophagy, insulin and other metabolic pathways;

- organelle alterations, like those occurring in nuclei, mitochondria, endocytic and autophagic compartments, endoplasmic reticulum, cytoskeleton components and extracellular matrix.

We would like to acknowledge that Dr. Alexandra Bottè, University of Texas MD Anderson Cancer Center, has acted as coordinators and have contributed to the preparation of the proposal for this Research Topic.


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Down syndrome is the most frequent genetic condition and the first chromosomal disorder for which the cause was identified: the presence of 3 copies of all or part of chromosome 21 (Hsa21). The molecular mechanisms that underlie the phenotypic alterations, especially cognitive impairment, are not yet fully elucidated. This is not surprising in light of the severity of the genetic alteration: the presence of an extra chromosome implies that there are three copies of more than 250 genes mapping to it, with a potential gene dosage problem for each of them.



A large number of transcriptomics studies has been conducted with the aim of identifying clusters of dysregulated genes, located either on Hsa21 or on other chromosomes, which operate in the same pathways or related ones. Their alterations could shed light on the molecular basis of a particular phenotypic abnormality. Transcriptomic studies have been carried out with different methodologies and on different tissues and cells. As a consequence, resulting data have often shown limited overlap, thus producing less interesting outcome than expected. In addition, recent studies have suggested that the presence of an extra chromosome in the nucleus can determine in itself a nuclear reorganization capable of altering gene expression independently on gene dosage.



Nevertheless, numerous studies have pursued the objective of clarifying the role of single Hsa21 genes in determining specific alterations at molecular, cellular and finally at phenotypic level. The attention has been preferentially focused on the genes mapping to the so-called ‘critical region for DS’, such as the dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1 A (DYRK1A), the regulator of calcineurin 1 (RCAN1), the cystathionine beta-synthase (CBS), the superoxide dismutase 1 (SOD1) and others. However, also genes outside the critical region have demonstrated to contribute to specific alterations. This is the case of the repressor gene NRIP1, which affects the expression of nuclear encoded mitochondrial genes and mitochondrial function. One should not neglect the effects of trisomy of Hsa21 non coding regions, which harbour microRNAs, as well as long noncoding RNAs and other RNA molecules, that may modulate target genes.



The aim of this Research Topic is to focus on those approaches that shed light on the molecular bases of DS, assuming that the dysregulation of one or more genes may perturb pathways that in turn affect organelle structure and function, thus producing phenotypic effects. The starting point can be investigating a gene, a pathway or an organelle, but the next important step will be to link them together to generate a holistic view of the processes in which they are involved and their role in the syndrome traits.



We welcome the submission of original research, brief research reports, and review manuscripts focusing on the following major facets of DS studies:



- multiomic approaches, such as genomic organization, transcriptome, proteome, epigenome, methylome, metabolome, etc;

- molecular pathways, such as respiration, energy conversion, ATP synthesis, ER stress, autophagy, insulin and other metabolic pathways;

- organelle alterations, like those occurring in nuclei, mitochondria, endocytic and autophagic compartments, endoplasmic reticulum, cytoskeleton components and extracellular matrix.

We would like to acknowledge that Dr. Alexandra Bottè, University of Texas MD Anderson Cancer Center, has acted as coordinators and have contributed to the preparation of the proposal for this Research Topic.


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

05 September 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

05 September 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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