High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network

Sgarra, Riccardo; Pegoraro, Silvia; D'Angelo, Daniela; Ros, Gloria; Zanin, Rossella; Sgubin, Michela; Petrosino, Sara; Battista, Sabrina; Manfioletti, Guidalberto

doi:10.3390/ijms21030717

Cited by 7 publications

(11 citation statements)

References 288 publications

(258 reference statements)

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“…A large volume of data demonstrates that miRNA dysregulation may intervene in tumor development [87,88]. Cancers exhibit distinctive miRNA expression signatures, raising the speculation that a dysregulation of specific pathways intervenes in tumorigenesis mechanisms in a specific tissue [89][90][91].…”

Section: Hmga Proteins In Oncologymentioning

confidence: 99%

“…Accordingly, HMGA2 seems to be a downstream modulator of the HSC self-renewal ability; its function is regulated by LIN28B, that acts as a master regulator of developmentally timed changes of HSC [93]. However, this regulatory mechanism seems to be even finer tuned [91]. In a recent work, Cesana et al employed high-throughput genomic approaches to profile miRNAs, long intergenic non coding RNAs (lincRNAs), and mRNAs in HSCs during development in order to characterize transcriptional and posttranscriptional changes [8].…”

Section: Hmga Proteins In Hematopoiesismentioning

confidence: 99%

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HMGA Proteins in Hematological Malignancies

Minervini

Coccaro

Anelli

et al. 2020

Cancers

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The high mobility group AT-Hook (HMGA) proteins are a family of nonhistone chromatin remodeling proteins known as “architectural transcriptional factors”. By binding the minor groove of AT-rich DNA sequences, they interact with the transcription apparatus, altering the chromatin modeling and regulating gene expression by either enhancing or suppressing the binding of the more usual transcriptional activators and repressors, although they do not themselves have any transcriptional activity. Their involvement in both benign and malignant neoplasias is well-known and supported by a large volume of studies. In this review, we focus on the role of the HMGA proteins in hematological malignancies, exploring the mechanisms through which they enhance neoplastic transformation and how this knowledge could be exploited to devise tailored therapeutic strategies.

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Section: Hmga Proteins In Oncologymentioning

confidence: 99%

Section: Hmga Proteins In Hematopoiesismentioning

confidence: 99%

HMGA Proteins in Hematological Malignancies

Minervini

Coccaro

Anelli

et al. 2020

Cancers

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“…(49) The need for tight control of HMGA2 expression is evidenced by its unusually complex regulatory circuitry including the cancer-associated let-7 miRNA and the HMGA2-overlapping pseudogene RPSAP52 and anti-sense gene HMGA2-AS1. (49,71) Importantly, another ncRNA gene, LINC02454, which exhibits an HMGA2-like expression pattern (Supplemental Fig. S10), is 9 kb downstream of the three Tier-1 SNPs in an ostb-associated super-enhancer far from HMGA2.…”

Section: Npr3 (Nprc) One Of the Tier-1 Snp Associated Genes Is Invomentioning

confidence: 99%

“…5) may be due to multiple miRNAs targeting HMGA2. (71) Besides a role for HMGA2 in negatively regulating MSC differentiation to ostb, it may play a protective role in the skeleton (73) at later steps in differentiation of ostb to osteocytes and in osteocyte homeostasis by helping to induce autophagy. (70,74,75) Like our five osteoporosis-risk candidate genes, the TFs predicted to bind to the Tier-1 SNPcontaining DNA sequences associated with these genes have special functions in the skeletal system (Supplemental Table S6).…”

Section: Npr3 (Nprc) One Of the Tier-1 Snp Associated Genes Is Invomentioning

confidence: 99%

Prioritization of osteoporosis-associated GWAS SNPs using epigenomics and transcriptomics

Zhang

Deng

Shen

et al. 2020

Preprint

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Genetic risk factors for osteoporosis, a prevalent disease associated with aging, have been examined in many genome-wide association studies (GWAS). A major challenge is to prioritize transcription-regulatory GWAS-derived variants that are likely to be functional. Given the critical role of epigenetics in gene regulation, we have used an unusual epigenetics-and transcription-based approach to identify credible regulatory SNPs relevant to osteoporosis from 38 reported BMD GWAS. Using Roadmap databases, we prioritized SNPs based upon their overlap with strong enhancer or promoter chromatin preferentially in osteoblasts relative to 11 heterologous cell culture types. The selected SNPs also had to overlap open chromatin (DNaseI-hypersensitive sites) and DNA sequences predicted to bind to osteoblast-relevant transcription factors in an allele-specific manner. From >50,000 GWAS-derived SNPs, we identified 16 novel and credible regulatory SNPs (Tier-1 SNPs) for osteoporosis risk. Their associated genes, BICC1, LGR4, DAAM2, NPR3, or HMGA2, are involved in osteoblastogenesis or bone homeostasis and regulate cell signaling or enhancer function. Four of them are preferentially expressed in osteoblasts. BICC1, LGR4, and DAAM2 play important roles in canonical Wnt signaling, a pathway critical to bone formation and repair. The transcription factors that are predicted to bind to the Tier-1 SNP-containing DNA sequences also have bone-related functions. For the seven Tier-1 SNPs near the 5' end of BICC1, examination of eQTL overlap and the distribution of BMD-increasing alleles suggests that at least one SNP in each of two clusters contributes to inherited osteoporosis risk. Our study not only illustrates a method that can be used to identify novel BMD-related causal regulatory SNPs for future study, but also reveals evidence that some of the Tier-1 SNPs exert their effects on BMD risk indirectly through little-studied noncoding RNA genes, which in turn may control the nearby bone-related proteinencoding gene.

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“…The mammalian high mobility group A (HMGA) chromosomal protein family encompasses HMGA1a and HMGA1b, encoded by HMGA1 gene via alternative splicing [5] and HMGA2 [6]. They are characterized by the ability to bind to DNA at AT-rich domains through their 'AT-hooks' regions.…”

Section: Introductionmentioning

confidence: 99%

HMGA1-Regulating microRNAs Let-7a and miR-26a are Downregulated in Human Seminomas

Martino

Esposito

Pellecchia

et al. 2020

IJMS

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Background: Recent studies have underlined HMGA protein’s key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the HMGA1 transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a—two HMGA1-targeting microRNAs. Methods: HMGA1 mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities. Results: an inverse correlation was found between the expression of miR-26a and Let-7a and HMGA1 expression levels in seminomas samples, suggesting a critical role of these microRNAs in HMGA1 levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2. Conclusions: these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is—at least in part—due to the downregulation of HMGA1-targeting microRNAs.

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High Mobility Group A (HMGA): Chromatin Nodes Controlled by a Knotty miRNA Network

Cited by 7 publications

References 288 publications

HMGA Proteins in Hematological Malignancies

HMGA Proteins in Hematological Malignancies

Prioritization of osteoporosis-associated GWAS SNPs using epigenomics and transcriptomics

HMGA1-Regulating microRNAs Let-7a and miR-26a are Downregulated in Human Seminomas

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