Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

Wang, Jerry C.; Ramaswami, Gokul; Geschwind, Daniel H.

doi:10.1101/2020.08.16.253377

Cited by 3 publications

(2 citation statements)

References 66 publications

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“…Such links to human disease have been particularly reinforced by many non-focal publications ( Table S3; Data Table S2 ). Indeed, expression of DUF34 in eukaryotes has been associated with several human pathologies, including cancers [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ], chemotherapeutic drug response [ 94 , 95 ], psychiatric disorders [ 96 , 97 ], cardiovascular disease [ 98 , 99 , 100 ], insulin resistance [ 101 ], osteoporosis [ 75 , 102 ], inflammation [ 103 ], Amyotrophic Lateral Sclerosis (ALS) [ 30 , 104 ], William-Beuren Syndrome [ 31 ], as well as several other degenerative and developmental neurological diseases [ 76 , 105 , 106 ]. The regulation of DUF34 homologs by retinoic acid or biochemical relatives (e.g., all-trans retinoic acid, ATRA; testosterone [Comparative Toxicogenomics Database]) appears to be conserved between humans, mice, and select life stages of some insects [ 73 , 107 , 108 , 109 ].…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomic Analysis of the DUF34 Protein Family Suggests Role as a Metal Ion Chaperone or Insertase

2021

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Members of the DUF34 (domain of unknown function 34) family, also known as the NIF3 protein superfamily, are ubiquitous across superkingdoms. Proteins of this family have been widely annotated as “GTP cyclohydrolase I type 2” through electronic propagation based on one study. Here, the annotation status of this protein family was examined through a comprehensive literature review and integrative bioinformatic analyses that revealed varied pleiotropic associations and phenotypes. This analysis combined with functional complementation studies strongly challenges the current annotation and suggests that DUF34 family members may serve as metal ion insertases, chaperones, or metallocofactor maturases. This general molecular function could explain how DUF34 subgroups participate in highly diversified pathways such as cell differentiation, metal ion homeostasis, pathogen virulence, redox, and universal stress responses.

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Section: Resultsmentioning

confidence: 99%

Comparative Genomic Analysis of the DUF34 Protein Family Suggests Role as a Metal Ion Chaperone or Insertase

2021

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“…Data Table 2). Indeed, expression of DUF34 in eukaryotes has been associated with several human pathologies, including cancers [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94], chemotherapeutic drug response [95,96], psychiatric disorders [97,98], cardiovascular disease [99][100][101], insulin resistance [102], osteoporosis [76,103], inflammation [104], Amyotrophic Lateral Sclerosis (ALS) [30,105], William-Beuren Syndrome [31], as well as several other degenerative and developmental neurological diseases [77,106,107]. The regulation of DUF34 homologs by retinoic acid or biochemical relatives (e.g., all-trans retinoic acid, ATRA; testosterone [Comparative Toxicogenomics Database]) appears to be conserved between humans, mice and select life stages of some insects [74,[108][109][110].…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomic Analysis of the DUF34 Protein Family Suggests Role as a Metal Ion Chaperone or Insertase

Reed¹,

Hutinet²,

Crécy‐Lagard³

2021

Preprint

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Members of the DUF34 (domain of unknown function 34) family, also known as the NIF3 protein superfamily, are ubiquitous across superkingdoms. Proteins of this family have been widely annotated as “GTP cyclohydrolase I type 2” through electronic propagation based on one study. Here, the annotation status of this protein family was examined through comprehensive literature review and integrative bioinformatic analyses that revealed varied pleiotropic associations and phenotypes. This analysis combined with functional complementation studies strongly challenges the current annotation and suggests that DUF34 family members may serve as metal ion insertases, chaperones, or metallocofactor maturases. This general molecular function could explain how DUF34 subgroups participate in highly diversified pathways such as cell differentiation, metal ion homeostasis, pathogen virulence, redox and universal stress responses.

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Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations

2021

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Luminal A is the most common breast cancer molecular subtype in women worldwide. These tumors have characteristic yet heterogeneous alterations at the genomic and transcriptomic level. Gene co-expression networks (GCNs) have contributed to better characterize the cancerous phenotype. We have previously shown an imbalance in the proportion of intra-chromosomal (cis-) over inter-chromosomal (trans-) interactions when comparing cancer and healthy tissue GCNs. In particular, for breast cancer molecular subtypes (Luminal A included), the majority of high co-expression interactions connect gene-pairs in the same chromosome, a phenomenon that we have called loss of trans- co-expression. Despite this phenomenon has been described, the functional implication of this specific network topology has not been studied yet. To understand the biological role that communities of co-expressed genes may have, we constructed GCNs for healthy and Luminal A phenotypes. Network modules were obtained based on their connectivity patterns and they were classified according to their chromosomal homophily (proportion of cis-/trans- interactions). A functional overrepresentation analysis was performed on communities in both networks to observe the significantly enriched processes for each community. We also investigated possible mechanisms for which the loss of trans- co-expression emerges in cancer GCN. To this end we evaluated transcription factor binding sites, CTCF binding sites, differential gene expression and copy number alterations (CNAs) in the cancer GCN. We found that trans- communities in Luminal A present more significantly enriched categories than cis- ones. Processes, such as angiogenesis, cell proliferation, or cell adhesion were found in trans- modules. The differential expression analysis showed that FOXM1, CENPA, and CIITA transcription factors, exert a major regulatory role on their communities by regulating expression of their target genes in other chromosomes. Finally, identification of CNAs, displayed a high enrichment of deletion peaks in cis- communities. With this approach, we demonstrate that network topology determine, to at certain extent, the function in Luminal A breast cancer network. Furthermore, several mechanisms seem to be acting together to avoid trans- co-expression. Since this phenomenon has been observed in other cancer tissues, a remaining question is whether the loss of long distance co-expression is a novel hallmark of cancer.

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Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

Cited by 3 publications

References 66 publications

Comparative Genomic Analysis of the DUF34 Protein Family Suggests Role as a Metal Ion Chaperone or Insertase

Comparative Genomic Analysis of the DUF34 Protein Family Suggests Role as a Metal Ion Chaperone or Insertase

Comparative Genomic Analysis of the DUF34 Protein Family Suggests Role as a Metal Ion Chaperone or Insertase

Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations

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