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Mis regulated Gene expression in disease - Module 5 Reading / Watching

Site: Justwrite
Course: An introduction to Gene Regulation and Gene Expression
Book: Mis regulated Gene expression in disease - Module 5 Reading / Watching
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Date: Saturday, 19 April 2025, 11:07 AM

Description

This Book Gives an overview of Module 5 and reference links 

Table of contents

1. Mis regulated Gene expression in disease

In this book you will see an overview of the topics of Module Five and reference links.

2. Learning Objectives

  • By the end of this chapter, readers will be able to:

    • Discuss the importance of gene expression regulation
    • Explain the link between dysregulated gene expression and cancer
    • Discuss the role of dysr



2.1. Altered Gene Expression and Cancer

Altered gene expression or dysregulated gene expression plays a role in the development of disease like Cancer. Proteins are turned on or expressed by gene activation and are turned off by gene silencing. This gene expression regulation determines the overall activity of the cell. A gene that is not normally expressed in a cell can be switched on and expressed at high levels due to  gene mutation or changes in gene regulation ( epigenetic, transcription, post-transcription, translation, or post-translation).Changes at each of these levels can be detected in different types of cancer  in different individuals. Scientific  studies had reported changes in histone acetylation , activation of transcription factors by phosphorylation, increased RNA stability, increased translational control, and protein modification etc.,  to be involved in the development of various cancers.

These are genes active in normal cells that function to prevent uncontrolled cellular proliferations example, p53 gene .This gene is  mutated in over 50 percent of all cancer types. The p53 protein itself functions as a transcription factor and can bind to promoters of genes to initiate transcription. Therefore, the mutation of p53 in cancer  alter the transcriptional activity of its target genes.

Proto-Oncogenes 

which are positive cell-cycle regulators. When mutated, proto-oncogenes can become oncogenes and cause cancer..

When their expression is deregulated in cancers  there can be overexpression and can become the oncogene  leading to uncontrolled cell growth. For example the Myc protein ,which is a transcription factor .Aberrantly activated  Myc results in  a cancer of the lymph system called  Overexpression of myc transforms normal B cells into cancerous cells that continue to grow uncontrollably and develop as tumors of the  jaw or  mouth that interfere with the ability to eat.

Epigenetic Alterations

Silencing genes through epigenetic mechanisms is also very common in cancer cells. Certain histone and DNA  modifications are associated with silenced genes. The DNA in the promoter region of silenced genes is methylated on cytosine DNA residues in CpG islands in most cancer cells.

Altered Transcription control

 Mutations may activate transcription factors and can increase the binding of a transcription factor to  a promoter. This could lead to increased transcriptional activation of that gene. This in turn  results in modified cell growth and proliferation. Also mutations in promoter or enhancer region can increase the binding ability of a transcription factor. This could also lead to the increased transcription and aberrant gene expression that is seen in cancer cells. For example Breast cancer cells over express the epidermal growth factor receptor (EGFR). The EGFR pathway activates many protein kinases that, in turn, activate many transcription factors that control genes involved in cell growth. Therefore  drugs that prevent the activation of EGFR have been developed  to treat breast cancer .

Altered expression of miRNAs

miRNAs bind to the 3′ UTR of RNA molecules and degrade them.  Overexpression of these miRNAs could be detrimental to normal cellular activity. Increased expression of  miRNAs could  decrease the RNA population and  in  turn decrease protein expression. Several studies have demonstrated  change in the miRNA population in specific cancer types. Aberrantly expressed miRNAs is also reported contributing to the pathogenesis of multiple sclerosis 

Altered Post translational control

Increased translation of a protein, changes in protein phosphorylation , variants of alternative splicing are found in cancer cells. For example ,the c-Flip protein ,  a protein involved in mediating the cell death pathway, exists in two forms: long (c-FLIPL) and short (c-FLIPS). In normal cells both the isoforms        appear to be involved in initiating controlled cell death mechanisms . However, in colon cancer cells,  long form  is seen to over expressed . This results in  increased cell growth instead of cell death. 



2.2. Dysregulated gene expression in Autoimmunity and Inflammation

Genetics and environmental factors are implicated in the pathogenesis of many autoimmune diseases. Increasing evidence has shown that dysregulated epigenetic modifications are involved in pathogenesis of several autoimmune diseases.

SLE is a multi-organ involved autoimmune disease  in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs. It can affect the joints, skin, brain, lungs, kidneys, and blood vessels. SLE is characterized by aberrant immune cells, such as dendritic cells, B and T lymphocytes.  Increasing evidence , have reported that DNA methylation plays a critical role in immune cells hyper-activation  in lupus conditions. Genomic DNA in lupus CD4+ T cells  has been found to show DNA hypomethylation. DNA hypomethylation is also reported in Lupus B cells.

Aberrant Histone Modifications is also contribute to Lupus. Lupus CD4+ T cells show global histone H3 and H4 hypoacetylation. Abnormal histone modifications have been found in the promoter region of TNFSF7 in T cells. This results in overexpression of CD70. This in turn might be the one cause of auto-reactivity of T cells. Histone hyperacetylation has been shown to be a cause for an increased serum level of TNF-α and an enhanced maturation status of monocytes from lupus patients.  miRNAs are also involved in the aberrant B cell expression and functions. Lupus B cells shows increased levels of miR-30a

Psoriasis

is a chronic inflammatory autoimmune skin disease. It is characterized by hyper proliferation of keratinocytes and dysregulated T cells, especially Th17 cells. Epigenetic regulations on immune cells also attributing to psoriasis pathogenesis. Aberrant DNA methylation pattern has also been revealed in CD4+ T cells from psoriatic patients, indicating  the role of epigenetic regulations.

 RA is an autoreactive immune cell-mediated inflammation which primarily affects joints. Autoreactive immune cells and synovial fibroblasts play an important role in the pathogenesis of RA. Increasing evidence has shown that DNA methylation contributes to the pathogenesis of RA. Global DNA hypomethylation is also found in T cells from RA patients

SSc is a relatively rare disease which is characterized by damages of connective tissues mediated by autoreactive immune cells. Its etiopathogenesis remains unclear. Abnormal epigenetic modifications have been shown in SSc. Dysregulated DNA methylation is indicated in Systemic Sclerosis.