Quantitative effects on gene silencing by allelic variation at a tetranucleotide microsatellite

Abstract

Microsatellites are common repeated sequences, which are useful as genetic markers and lack any clearly established function. In a previous study we suggested that an intronic polymorphic TCAT repeat in the tyrosine hydroxylase (TH) gene, the microsatellite HUMTH01, may regulate transcription. The TH gene encodes the rate-limiting enzyme in the synthesis of catecholamines, and the microsatellite HUMTH01 has been used in genetic studies of neuropsychiatric and cardiovascular diseases, in which disturbances of catecholaminergic neurotransmission have been implicated. HUMTH01 alleles associated with these diseases act as transcriptional enhancers when linked to a minimal promoter and are recognized by specific nuclear factors. Here we show that allelic variations of HUMTH01 commonly found in humans have a quantitative silencing effect on TH gene expression. Two specific proteins, ZNF191, a zinc finger protein, and HBP1, an HMG box transcription factor, which bind the TCAT motif, were then cloned. Finally, allelic variations of HUMTH01 correlate with quantitative and qualitative changes in the binding by ZNF191. Thus, this repeated sequence may contribute to the control of expression of quantitative genetic traits. As the HUMTH01 core motif is ubiquitous in the genome, this phenomenon may be relevant to the quantitative expression of many genes in addition to TH.

Association of TH01 with human longevity revisited

“…If the TH01 STR is selectively neutral, the observed cline could be a consequence of past migrations or random genetic drift. But since the STR may regulate gene transcription in an allele-specific manner 21 and may therefore be phenotypically relevant, the geographic allele distribution might very well reflect the adaptation to different environments and selective pressures. More detailed functional studies together with population genetic analyses are necessary to clarify this question.…”

The influences on human longevity by HUMTHO1.STR polymorphism (Tyrosine Hydroxylase gene)

“…This system governs the capability to cope with a variety of stress-factors and, consequently, rate and quality of aging . The HUMTHO1 microsatellite acts, in vitro, as a transcription regulatory element showing a silencing effect which correlates with the number of repetitions (Meloni et al, 1998;Albanese et al, 2001). In particular, the inhibition is proportional to the number of repeats up to allele 8, while by increasing the number of repeats up to 10, no further inhibitory effect is observed, but rather a relative enhancement depending on the cell lines used (Albanese et al, 2001).…”

“…The HUMTHO1 microsatellite acts, in vitro, as a transcription regulatory element showing a silencing effect which correlates with the number of repetitions (Meloni et al, 1998;Albanese et al, 2001). In particular, the inhibition is proportional to the number of repeats up to allele 8, while by increasing the number of repeats up to 10, no further inhibitory effect is observed, but rather a relative enhancement depending on the cell lines used (Albanese et al, 2001). These findings support the idea that HUMTHO1 microsatellite regulates TH transcription in an allelicspecific way, and modulates the activity of the TH gene acting as a quantitative genomic effector.…”

Association tests with systemic lupus erythematosus (SLE) of IL10 markers indicate a direct involvement of a CA repeat in the 5′ regulatory region

“…[39][40][41][42][43] The number of tandem repeats has been shown to influence the transcription rate either by a direct interaction with a transcription factor 44,45 or by affecting spacing between flanking regions. 46 Considering the data of the present paper it is tempting to speculate that a long IL10.G allele might be responsible for a high IL10 production, a typical aspect of SLE pathogenesis.…”