Molecular implications of HOX genes targeting multiple signaling pathways in cancer

Shenoy, U Sangeetha; Adiga, Divya; Kabekkodu, Shama Prasada; Hunter, Keith D.; Radhakrishnan, Raghu

doi:10.1007/s10565-021-09657-2

Cited by 17 publications

(13 citation statements)

References 226 publications

(223 reference statements)

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“…Hoxa1, the most 3' member of the Hoxa cluster, is a direct RA target and a master regulator of mouse embryogenesis 52 . In humans, its overexpression correlates with tumor cell proliferation in different types of cancer [30][31][32]53 .…”

Section: Discussionmentioning

confidence: 99%

Inferring the Hoxa1 Gene Regulatory Network in Mouse Embryonic Stem Cells: Time-Series RNA-seq Data and Computational Modeling Approach

Emelogu,

Rogers,

Banad

et al. 2023

Preprint

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The homeotic gene Hoxa1 plays a pivotal role in regulating embryonic pattern formation and morphogenesis during mouse embryogenesis. However, despite the identification of a number of putative Hoxa1 target genes, the intricate regulatory relationships between these targets remain largely elusive. Leveraging the advancements in high-throughput technologies and sophisticated computational methods, we aimed to infer the Gene Regulatory Networks (GRNs) governed by Hoxa1 that direct cellular function, morphology, and/or differentiation. To achieve this, we generated time-series RNA-seq data from Retinoic Acid (RA)-treated Wild Type versus Hoxa1-null mouse ES cells, enabling the construction of the Hoxa1 GRN. To create this GRN, we employed NARROMI, a published technique known for its noise reduction capabilities and improved accuracy in gene-regulation inference. Using this technique, we identified putative direct and indirect connections between Hoxa1 and a set of genes with known relevance in embryonic development. Validation through qPCR confirmed the Hoxa1-dependence on mRNA expression for selected genes, both within the immediate vicinity (direct) and in secondary interactions (indirect). Furthermore, by mapping the candidate genes to relevant Gene Ontology (GO) networks, we verified their involvement in processes likely regulated by Hoxa1. Our findings provide compelling evidence supporting the accuracy of the NARROMI analysis in generating a hierarchical network of genes under the transcriptional control of Hoxa1 Transcription Factor (TF), specifically in mouse ES cells. This network reveals a pool of promising candidate genes that may function as direct targets of Hoxa1. However, further investigations, including the characterization of Hoxa1 protein interactions with target loci DNA, are necessary to confirm their direct regulatory relationship with this TF. Moreover, the time-series RNA-seq data from Wild Type ES cells, coupled with the methodology employed in this study, hold the potential for constructing GRNs for additional TFs activated by RA. This comprehensive approach can shed further light on the intricate regulatory networks governing cellular function, morphology, and differentiation, advancing our understanding of embryonic development and gene regulation processes.

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Section: Discussionmentioning

confidence: 99%

Inferring the Hoxa1 Gene Regulatory Network in Mouse Embryonic Stem Cells: Time-Series RNA-seq Data and Computational Modeling Approach

Emelogu,

Rogers,

Banad

et al. 2023

Preprint

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“…HOXC6 promotes cell proliferation via the activation of the MAPK pathway ( Yang et al, 2019 ). Other HOX genes, such as HOXD4 , are also implicated in MAPK signaling pathway alterations and affect benign or malignant hematopoiesis ( Shenoy et al, 2022 ). MicroRNAs play a major epigenetic role in the regulation of hematopoiesis via different signaling pathways ( Shen et al, 2008 ; Yao et al, 2019 ).…”

Section: Changes In Specific Hox Mrna Expression Levels Due To Post-t...mentioning

confidence: 99%

MicroRNA target homeobox messenger RNA in HIV induced hematopoietic inhibition

Koka,

Ramdass

2024

Front. Cell Dev. Biol.

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Cytopenias are a common occurrence due to abnormal hematopoiesis persistent in patients suffering from and advancing with HIV/AIDS. In order to develop efficacious therapies against cytopenias, it is necessary to understand the mechanisms by which HIV infection affects the differentiation of hematopoietic stem-progenitor cells (HSPCs), causing hematopoietic inhibition, that leads to hematological disorders. Currently, only the antiretrovirals that are being used to treat HIV infection and indirectly lower the levels of virus replication also co-attenuate cytopenias. The evidence available suggests that this indirect efficacy may not prevail for the lifetime of the infected patients, and the acquired immunodeficiency can overtake the beneficial consequences of decreased virus replication. As cited in this article, we and our colleagues are the first to make a foray into the involvement of microRNAs and their use as potential interventional treatments for the cytopenias that occur with HIV/AIDS. Herein, we progressed further in the direction of the mechanisms of the involvement of homeobox gene regulation to cause cytopenias. We had previously shown that HIV-1 inhibits multi-lineage hematopoiesis of the CD34+ cells using SCID-hu Thy/Liv animals in vivo. Furthermore, we demonstrated that the virus-induced hematopoietic inhibition occurred despite the CD34+ cells being resistant to HIV-1 infection. We set out to search for the specific host factors secreted by CD4+ T-cells that likely participate in the inhibition of hematopoiesis of the HIV infection-resistant CD34+ cells. More recently, we reported the identification of virus-infected CD4+ thymocyte-secreted miRNA-15a and miRNA-24 and that their differential expression following HIV infection causes the indirect inhibition of hematopoiesis. We then hypothesized that the observed miRNA differential expression in the virus-infected T-cells causes the abnormal regulation of homeobox (HOX) gene-encoded transcriptomes in the CD34+ cells, affecting specific MAPK signaling and CD34+ cell fate, thereby disrupting normal hematopoiesis. We present that in HIV infection, miRNA-mediated post-transcriptional dysregulation of HOXB3 mRNA inhibits multi-lineage hematopoiesis, which translates into hematological disorders in virus-infected patients with HIV/AIDS. These observations portend specific microRNA candidates for potential efficacy against the virus-induced cytopenias that are otherwise not treatable by the existing HAART/ART regimens, which are primarily designed and applicable for the attenuation of virus replication.

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“…Similarly, HOXA5, HOXB5, HOXB6, HOXB7, and other HOX family genes showed hypermethylation in the promoter region in DOK and CAL-27 cells. The mammalian HOX family is divided into four subfamilies, namely A, B, C, and D. Human HOX genes are located on chromosomes 7, 17, 12, and 2, with a total of 39 members (37). The HOX protein is by the HOX gene, which serves with diverse functions in different cellular environments.…”

Section: Current Studies On Dmr-related Genesmentioning

confidence: 99%

Whole-genome bisulfite sequencing reveals the alteration of DNA methylation during malignant transformation of oral mucosal cells

Wang

Sun

et al. 2023

Preprint

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Background According to recent researches, the overall malignant transformation rate of oral potentially malignant disorders (OPMDs) is among 7.9%, and the probability of malignant transformation of OPMDs with severe epithelial dysplasia to oral squamous cell carcinoma (OSCC) is as high as 57%. In recent years, more and more studies have confirmed that abnormal DNA methylation, especially hypermethylation of the promoter CpG islands, is closely related to the occurrence and malignant transformation of OPMDs. Hypermethylation of certain tumor suppressor genes can be used as a key indicator for diagnosing early OSCC and judging the prognosis of OPMDs. There is an urgent need to expand the understanding of DNA methylation alterations occurred in OPMDs and OSCC at the cellular level. Methods and results We used the Illumina sequencing platform to perform the whole-genome bisulfite sequencing （WGBS）on dysplastic oral keratinocyte (DOK) and CAL-27 cell lines, which respectively represents epithelial dysplasia and carcinogenesis. Then we compared the results with trends in human gingival fibroblasts (HGFs) to identify differentially methylated regions (DMRs). Gene Oncology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to further explore the biological functions and signaling pathways related to the observed differences. Compared with those in HGFs, respectively 4,149 and 2,863 genes were abnormally hypermethylated in DOK and CAL-27 cells in the promoter CG context. GO and KEGG analyses showed that the identified differentially methylated genes were involved in system development, transcriptional regulation, cell differentiation, and other pathways (e.g., autophagy, mitophagy, and cAMP signaling). Conclusions Our results expand on the knowledge of DNA methylation alterations associated with OPMDs and OSCC at the cellular level. The key genes and pathways involved in the regulatory mechanisms of DNA methylation may provide a theoretical basis for research on the malignant transformation of OPMDs as well as for the early diagnosis and treatment of oral squamous cell carcinoma.

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Molecular implications of HOX genes targeting multiple signaling pathways in cancer

Cited by 17 publications

References 226 publications

Inferring the Hoxa1 Gene Regulatory Network in Mouse Embryonic Stem Cells: Time-Series RNA-seq Data and Computational Modeling Approach

Inferring the Hoxa1 Gene Regulatory Network in Mouse Embryonic Stem Cells: Time-Series RNA-seq Data and Computational Modeling Approach

MicroRNA target homeobox messenger RNA in HIV induced hematopoietic inhibition

Whole-genome bisulfite sequencing reveals the alteration of DNA methylation during malignant transformation of oral mucosal cells

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