Solution structure of the MEF2A-DNA complex: structural basis for the modulation of DNA bending and specificity by MADS-box transcription factors

131

Gene duplication is a substrate of evolution. However, the relative importance of positive selection versus relaxation of constraints in the functional divergence of gene copies is still under debate. Plant MADS-box genes encode transcriptional regulators key in various aspects of development and have undergone extensive duplications to form a large family. We recovered 104 MADS sequences from the Arabidopsis genome. Bayesian phylogenetic trees recover type II lineage as a monophyletic group and resolve a branching sequence of monophyletic groups within this lineage. The type I lineage is comprised of several divergent groups. However, contrasting gene structure and patterns of chromosomal distribution between type I and II sequences suggest that they had different evolutionary histories and support the placement of the root of the gene family between these two groups. Site-specific and sitebranch analyses of positive Darwinian selection (PDS) suggest that different selection regimes could have affected the evolution of these lineages. We found evidence for PDS along the branch leading to flowering time genes that have a direct impact on plant fitness. Sites with high probabilities of having been under PDS were found in the MADS and K domains, suggesting that these played important roles in the acquisition of novel functions during MADS-box diversification. Detected sites are targets for further experimental analyses. We argue that adaptive changes in MADSdomain protein sequences have been important for their functional divergence, suggesting that changes within coding regions of transcriptional regulators have influenced phenotypic evolution of plants.ene duplication provides a substrate for evolution, and understanding the fate of duplicates is fundamental to clarifying mechanisms of genetic redundancy and the link between gene family diversification and phenotypic evolution (1). Several empirical studies have evaluated the roles of duplication in adaptation and diversification (2), but the evolutionary forces at play during functional divergence of duplicates are still under debate (3, 4). Genomic studies are revealing that eukaryotes harbor large families of genes that have arisen during evolution through duplication and have persisted for longer periods of time than expected by classical models (5). Models that incorporate positive selection (6, 7) provide alternative explanations for the persistence of duplicates.Empirical studies to test models on the fate of duplicates and the evolutionary forces driving their functional divergence will need complete and resolved gene family phylogenies. Several studies suggest that positive Darwinian selection (PDS) might have been important in protein evolution. However, most previous studies have involved few members of a gene family from various species (8,9). In this article, we annotate, align, and analyze the complete MADS-box gene family of the plant model system Arabidopsis thaliana and provide resolved phylogenies as a basis to infer the role of PDS in protein ...

Section: Discussionmentioning

confidence: 70%

Section: Mads-box Gene Family Phylogenymentioning

confidence: 99%

See 1 more Smart Citation

Adaptive evolution in the Arabidopsis MADS-box gene family inferred from its complete resolved phylogeny

Martínez-Castilla

Álvarez-Buylla²

2003

131

“…The binding of a dimer of serum response factor (SRF) to an A͞T-rich site and subsequent recruitment of the ets factor Elk-1 to a GGA core sequence to form a ternary complex (TC) is required for c-fos transcription (11). Both TFs primarily bind DNA in the major groove but make minor groove contacts (12,13). This mode of binding and the presence of an A͞T-rich site make these TFs potential targets for MGTs.…”

mentioning

confidence: 99%

Inhibition of transcription factor-DNA complexes and gene expression by a microgonotropen

White

Satz

Bruice

et al. 2001

Developing minor groove-binding drugs to selectively inhibit transcription factor (TF)͞DNA interactions and accompanying gene expression is a current goal in drug development studies. Equipping minor groove-binding agents with positively charged, major groove-contacting side chains yields microgonotropens (MGTs). Previously, we demonstrated that MGTs were superior inhibitors of TF͞DNA complexes in cell-free assays compared with ''classical'' groove binders, but MGTs showed limited ability to inhibit gene expression. To determine what chemical characteristics contribute to or improve activity, we evaluate five MGTs for their effectiveness in inhibiting TF complex formation and resultant transcription by using the c-fos serum response element (SRE) as a target. MGT L1 binds DNA via a bisbenzimidazole equipped with a tripyrrole moiety. It is compared with analog L2, which has been functionalized with propylamines on each of the three pyrroles. L2, which binds DNA at subpicomolar concentrations, was at least three orders of magnitude more potent than L1 at inhibiting TF binding to the c-fos SRE in cell-free assays. Unlike L1 and previous MGTs, L2 also inhibited endogenous c-fos expression in NIH 3T3 cells at micromolar levels. Structure͞activity relationships suggest that, although the tripyrrole͞polyamine functional group of L2 may be largely responsible for its inhibition of TF complexes in cell-free assays, its bisbenzimidazole moiety appears to impart improved cellular uptake and activity. These findings make L2 a promising lead candidate for future, rational MGT design.

“…2 E and F). Our group has previously shown-via reporter gene assays, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay-that posttranslational redox modification of Cys39 inhibits MEF2 transcriptional activity by interfering with DNA binding (27,28,35,36). Hence, it might be expected that excessive ROS exposure would lead to the formation of SO X H-MEF2D (x = 1-3), thereby impairing transcription of MEF2 target genes.…”

Section: Mef2dmentioning

confidence: 99%

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Nagar

Noveral

Trudler

et al. 2017

Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d +/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of lightinduced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.B lindness due to photoreceptor loss from a number of diseases is a prevalent and devastating condition in the human population. Genetic predisposition and environmental stress play major roles in the incidence and progression of the retinal degeneration. Understanding disease mechanisms and interactions of causative factors should help in the design of treatment strategies. Recent evidence indicates that oxidative stress, contributing to photoreceptor cell death, plays a significant role in the pathophysiology of nonsyndromic retinitis pigmentosa (RP) and possibly age-related macular degeneration (AMD) (1-3). Moreover, light-induced oxidative stress is known to potentiate photoreceptor loss in genetic models mimicking a number of human retinal degenerations (4-11).The oxidizing microenvironment of the retinal pigment epithelium (RPE)-photoreceptor complex has been predominantly attributed to high oxygen demand, abundant polyunsaturated fatty acids, and direct exposure to light, coupled with the adjacent choroidal hemodynamics (12). Light exposure compounded over many years in the presence of photosensitizers may prime photoreceptors and RPE for free radical/oxidative damage (12-14). In some animal models of photoreceptor degeneration, including RP and Leber congenital amaurosis, disease progression is accelerated by exposure to light and slowed by rearing in darkness (3, 15). Advanced age also compromises the endogenous antioxidant ...