The Expression of the Avian Clusterin Gene can be Driven by two Alternative Promoters with Distinct Regulatory Elements

Abstract Integration of retroviral vectors in the human genome follows nonrandom patterns that favor insertional deregulation of gene expression and increase the risk of their use in clinical gene therapy. The molecular basis of retroviral target site selection is still poorly understood. We used deep sequencing technology to build genomewide, high-definition maps of > 60 000 integration sites of Moloney murine leukemia virus (MLV)– and HIV-based retroviral vectors in the genome of human CD34+ multipotent hematopoietic progenitor cells (HPCs) and used gene expression profiling, chromatin immunoprecipitation, and bioinformatics to associate integration to genetic and epigenetic features of the HPC genome. Clusters of recurrent MLV integrations identify regulatory elements (alternative promoters, enhancers, evolutionarily conserved noncoding regions) within or around protein-coding genes and microRNAs with crucial functions in HPC growth and differentiation, bearing epigenetic marks of active or poised transcription (H3K4me1, H3K4me2, H3K4me3, H3K9Ac, Pol II) and specialized chromatin configurations (H2A.Z). Overall, we mapped 3500 high-frequency integration clusters, which represent a new resource for the identification of transcriptionally active regulatory elements. High-definition MLV integration maps provide a rational basis for predicting genotoxic risks in gene therapy and a new tool for genomewide identification of promoters and regulatory elements controlling hematopoietic stem and progenitor cell functions.

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Structure and alternative promoters of the mouse glutamic acid decarboxylase 67 gene

Biochemical Journal ◽

10.1042/bj3260573 ◽

1997 ◽

Vol 326 (2) ◽

pp. 573-578 ◽

Cited By ~ 32

Author(s):

Yuchio YANAGAWA ◽

Takashi KOBAYASHI ◽

Takashi KAMEI ◽

Kenji ISHII ◽

Michiharu NISHIJIMA ◽

...

Keyword(s):

Glutamic Acid ◽

Glutamic Acid Decarboxylase ◽

Single Gene ◽

Regulatory Elements ◽

Acid Decarboxylase ◽

Alternative Promoters ◽

Promoter Regions ◽

Genomic Clones ◽

Exon 1 ◽

Rapid Amplification

γ-Aminobutyric acid is synthesized by glutamic acid decarboxylase (GAD), which has two forms, GAD65 and GAD67. Genomic clones coding mouse GAD67 (mGAD67) have been isolated. The restriction map of the overlapping clones covers a region of more than 45 kb of genomic DNA. The mGAD67 gene contains 16 translated exons in addition to an exon which is preferentially expressed in foetal brain. The rapid amplification of 5′-cDNA ends showed that mGAD67 gene transcripts have two different 5′-untranslated regions. Analysis of the genomic clones encompassing the 5′-exons revealed that the two transcripts arose from a single gene by alternative splicing using two different donor sites and a common acceptor. The exons were found 1.5 and 0.6 kb upstream of exon 1. The corresponding promoter regions of these exons have a number of putative regulatory elements, including Sp1- and Krox-24-binding sites. Analysis of mGAD67 transcripts demonstrated that each of the 5′-untranslated exons was expressed in mouse brain. In contrast, exon 0A, but not exon 0B, was expressed in mouse testis and pancreas. These results suggest that these transcripts may be regulated under the control of independent promoters.

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[P1.87]: Two regulatory elements with opposite effects modulate the activity of prrxl1 alternative promoters

International Journal of Developmental Neuroscience ◽

10.1016/j.ijdevneu.2010.07.127 ◽

2010 ◽

Vol 28 (8) ◽

pp. 684-684

Author(s):

I. Regadas ◽

F. Monteiro ◽

S. Rebelo ◽

D. Lima ◽

C. Reguenga

Keyword(s):

Regulatory Elements ◽

Alternative Promoters

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Nutrient and hormonal regulation of pyruvate kinase gene expression

Biochemical Journal ◽

10.1042/bj3370001 ◽

1998 ◽

Vol 337 (1) ◽

pp. 1-11 ◽

Cited By ~ 77

Author(s):

Kazuya YAMADA ◽

Tamio NOGUCHI

Keyword(s):

Pyruvate Kinase ◽

Hormonal Regulation ◽

Regulatory Elements ◽

Glycolytic Enzyme ◽

Hormonal Control ◽

Nuclear Factor ◽

Alternative Promoters ◽

Kinase Gene ◽

Flanking Region ◽

Nuclear Factor 1

Mammalian pyruvate kinase (PK), a key glycolytic enzyme, has two genes named PKL and PKM, which produce the L- and R-type isoenzymes by means of alternative promoters, and the M1-and M2-types by mutually exclusive alternative splicing respectively. The expression of these genes is tissue-specific and under developmental, dietary and hormonal control. The L-type isoenzyme (L-PK) gene contains multiple regulatory elements necessary for regulation in the 5´ flanking region, up to position -170. Both L-II and L-III elements are required for stimulation of L-PK gene transcription by carbohydrates such as glucose and fructose, although the L-III element is itself responsive to carbohydrates. The L-II element is also responsible for the gene regulation by polyunsaturated fatty acids. Nuclear factor-1 proteins and hepatocyte nuclear factor 4, which bind to the L-II element, may also be involved in carbohydrate and polyunsaturated fatty acid regulation of the L-PK gene respectively. However, the L-III-element-binding protein that is involved in carbohydrate regulation remains to be clarified, although involvement by an upstream stimulating factor has been proposed. Available evidence suggests that the carbohydrate signalling pathway to the L-PK gene includes a glucose metabolite, possibly glucose 6-phosphate or xylulose 5-phosphate, as well as phosphorylation and dephosphorylation mechanisms. In addition, at least five regulatory elements have been identified in the 5´ flanking region of the PKM gene up to position -279. Sp1-family proteins bind to two proximal elements, but the binding of proteins to other elements have not yet been clarified. Glucose may stimulate the transcription of the PKM gene via hexosamine derivatives. Sp1 may be involved in this regulation via its dephosphorylation, although the carbohydrate response element has not been determined precisely in the PKM gene. Thus glucose stimulates transcription of the PKM gene by the mechanism which is probably different from the L-PK gene.

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Differential epigenetic regulation between the alternative promoters, PRDM1α and PRDM1β, of the tumour suppressor gene PRDM1 in human multiple myeloma cells

Scientific Reports ◽

10.1038/s41598-020-72946-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Raquel Romero-García ◽

Laura Gómez-Jaramillo ◽

Rosa María Mateos ◽

Gema Jiménez-Gómez ◽

Nuria Pedreño-Horrillo ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Lines ◽

Plasma Cells ◽

Regulatory Elements ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Alternative Promoters ◽

Therapeutic Approaches ◽

Human Multiple Myeloma

Abstract Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the accumulation of malignant plasma cells in the bone marrow. The transcription factor PRDM1 is a master regulator of plasma cell development and is considered to be an oncosuppressor in several lymphoid neoplasms. The PRDM1β isoform is an alternative promoter of the PRDM1 gene that may interfere with the normal role of the PRDM1α isoform. To explain the induction of the PRDM1β isoform in MM and to offer potential therapeutic strategies to modulate its expression, we characterized the cis regulatory elements and epigenetic status of its promoter. We observed unexpected patterns of hypermethylation and hypomethylation at the PRDM1α and PRDM1β promoters, respectively, and prominent H3K4me1 and H3K9me2 enrichment at the PRDM1β promoter in non-expressing cell lines compared to PRDM1β-expressing cell lines. After treatment with drugs that inhibit DNA methylation, we were able to modify the activity of the PRDM1β promoter but not that of the PRDM1α promoter. Epigenetic drugs may offer the ability to control the expression of the PRDM1α/PRDM1β promoters as components of novel therapeutic approaches.

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The atlas of human cardiac promoters and enhancers reveals an important role for regulatory elements in heart failure

10.21203/rs.3.rs-1010746/v1 ◽

2021 ◽

Author(s):

Ruslan Deviatiiarov ◽

Anna Gams ◽

Roman Syunyaev ◽

Tatiana Tatarinova ◽

Ramesh Singh ◽

...

Keyword(s):

Heart Failure ◽

Regulatory Network ◽

Regulatory Elements ◽

Nucleotide Polymorphisms ◽

Alternative Promoters ◽

Continuous Increase ◽

Regulatory Changes ◽

Cap Analysis ◽

Failing States ◽

Transcriptomic Changes

Abstract A continuous increase in the prevalence of heart failure and the lack of adequate therapy highlight poor understanding of the underlying genetic regulatory mechanisms involved in heart failure pathogenesis. Growing evidence has demonstrated a significant contribution of non-coding genome regulatory elements towards transcriptomic changes in heart disease. Thus, there is a pressing need for a comprehensive resource of the human cardiac regulatory network in healthy and failing states. We applied cap analysis of gene expression sequencing to directly measure the expression of RNA associated with enhancers and promoters. Based on this data, we constructed the atlas of transcribed cardiac regulatory elements from 21 healthy and 10 failing (ischemic and non-ischemic cardiomyopathy) human hearts. In total, we have sequenced 109 samples from the left and right atria and ventricles, identifying 17,668 promoters and 14,920 enhancers associated with 14,519 genes. Leveraging this atlas, we provide insights into functional and structural regulatory changes between healthy and failing hearts. Healthy atria and ventricles had distinct pathway enrichment and transcription factor binding patterns, significantly remodeled by heart failure. Using the advantages of deep sequencing that allow effective analysis of cis-regulatory elements-derived RNA, we found that heart failure is associated with the expression of transcripts derived from alternative promoters and a specific set of transcribed enhancers. Furthermore, we identified a high prevalence of single nucleotide polymorphisms associated with cardiovascular diseases within the regulatory regions highlighting their importance in disease pathogenesis. This open-source atlas will serve the cardiovascular community to improve understanding cardiac regulatory network and facilitate the development of novel therapeutics.

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Hungarian small business tax and possibilities to minimize distortions from capital income taxation

Society and Economy ◽

10.1556/204.2015.37.s.6 ◽

2015 ◽

Vol 37 (s1) ◽

pp. 87-105

Author(s):

Benedek Nobilis ◽

András Svraka

Keyword(s):

Small Business ◽

Cash Flow ◽

Capital Accumulation ◽

Value Added ◽

Regulatory Elements ◽

Capital Income ◽

Potential Growth ◽

Elegant Method ◽

Business Tax ◽

Working Out

Governments throughout the EU and OECD countries rely on revenues raised on capital income. Albeit several arguments can be made for keeping these taxes, in their widespread form they hinder capital accumulation and significantly lower potential growth due to their savings and investment distorting nature. At the same time, the actual economic impact of tax types is largely influenced by their structure. An elegant method, which is also simple in its concept, for eliminating the economic distortions of profit taxes is cash-flow taxation which moves income taxes closer to the more growth-friendly value-added taxes. The small business tax, which was introduced in Hungary in 2013, was designed along these principles. In this paper we review the theoretical literature on cash-flow taxation and discuss the main regulatory elements of the small business tax, as well as the solutions elaborated for working out the challenges related to its implementation.

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