Biology subjects

Yilmaz, Z.

Publications and source records attributed to Yilmaz, Z..

9 recordsLinked to original sources

bioRxiv2025

A Cysteine-Less and Ultra-Fast Split Intein Rationally Engineered from Being Aggregation-Prone to Highly Efficient in Protein trans-Splicing

Split inteins ligate their fused extein protein sequences while undergoing self-removal. This unique protein trans-splicing reaction has been harnessed for numerous applications in protein modification. However, several purified split intein precursors splice only partially or are entirely inactive for unknown reasons. We have studied the split Aes123 PolB1 intein, which splices only to about 30%. As a rare representative of cysteine-less split inteins, the Aes intein is attractive due to its resistance to oxidative conditions and orthogonality to thiol chemistries. We revealed that the reduced splicing efficiency is caused by the formation of soluble, {beta}-sheet dominated aggregates of the N-terminal precursor. We computationally, biochemically and biophysically characterized the fully active monomeric fraction to identify sequence regions important for aggregation. Guided by a crystal structure we designed stably monomeric mutants with virtually complete splicing activity. The triple mutant CLm intein (Cysteine-Less and monomeric) retained the ultra-fast rate discovered for the wildtype and exhibits superior utility as a thiol-independent protein modification tool. Characterization of two other benchmark split inteins suggests that the discovered aggregation propensity reflects an inherent challenge to keep the split intein precursor in the partially disordered form required to fold with its complementary partner into the active complex.

biochemistry↗

bioRxiv2024

Analysis of RNA/DNA Hybrid Profiles in Blood From Autistic Patients Reveals Differences in mRNA and non-coding RNA Regions

DNA/RNA hybrids are present in normal cellular physiology, but when misregulated in the genome, they can contribute to human pathologies such as neurodevelopmental disorders and cancer. These hybrid structures are often abundant in repetitive genomic sequences such as telomeres and centromeres, contributing to evolutionary conserved phenomena. However, excessive accumulation can lead to DNA damage and genomic instability. Studies of autism spectrum disorders (ASDs) have revealed genome-wide disruptions, including mutations and significant deregulation of gene expression. Surprisingly, the common underlying factors remain unidentified. ASDs, which are of hereditary origin and more prevalent among boys, manifest themselves during development through disorders of various origins. In this study, we used whole-genome transcriptomic analysis of DNA/RNA hybrids from blood samples of autistic patients and healthy controls. we identified differences between numerous hybrid genomic regions with varying sequence compositions. Additionally, we observed local specificity in genomic regions, where RNA could either inhibit or enhance transcription. Our analysis of short RNAs hybridized with DNA revealed a striking example of transcriptional activity, where each gene is stably transcribed. We propose that non-coding RNAs originating from exons, introns or intergenic regions bind to DNA as hybrids (DNA/RNA) and influence gene expression. The specific levels of these short RNAs may regulate their own transcription, likely affecting cell fate.

molecular biology↗

bioRxiv2024

Head trauma impairs HPA-axis functions by increased R-loop structure and shortens telomeres

Traumatic brain injury (TBI) causes inflammation, one of the main causes of cellular aging. Telomere repeat-containing RNA (TERRA) hybridizes to telomere regions, forming R-loop structures and ensuring genome stabilization. Deregulation of R-loop homeostasis leads to genomic instability linked to neurodegenerative diseases and cancer. The hypothalamus-pituitary-adrenal (HPA) axis response is critical to maintaining homeostasis after TBI. We showed that the local increase in the transcription levels of the Crh and Pomc genes, in particular, suggests a defensive response through transcriptional alteration against mild TBI despite the decreased rate in the serum in the chronic phase. Additionally, changes in the transcription levels of TERRA and correlations with hormonal deficits after repetitive mTBI head trauma were observed. Telomere shortening and increased hybridized TERRA levels, especially after repeated mTBI in the chronic phase, suggest a possible disorder of genome stabilization and loss of cellular function in tissues of the hypothalamus, pituitary, and adrenal glands.

genomics↗

bioRxiv2022

Progressive decline in the levels of six miRNAs from parents to children in autism

The growing burden of a gradual increase in births of children with autism has placed it at the center of the concerns of major laboratories. We have previously detected a decrease in the levels of six miRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) in parents and their children inherited at a lower level. Here, we suggest that down-regulation of each of these six miRNAs inherited from parents contributes to the development of children with autism. We compare their levels of distribution in each family between the autistic child and siblings. We find that the distribution of levels of these miRNAs in siblings (undiagnosed as autism) is not always higher than in autistic children, but it is at varying levels. These data support a model in which autistic behavior relies on low levels of the six miRNAs expressed in children potentially associated with autistic syndrome (ASD). The intimate link between miRNAs levels and behavioral characteristics suggests possibilities for understanding the basic circuitry involved in autism and thus advancing partial knowledge of brain functions. An early diagnosis of autism helps provide children an environment conducive to their development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/512859v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@176d6f4org.highwire.dtl.DTLVardef@11a4ebforg.highwire.dtl.DTLVardef@280f67org.highwire.dtl.DTLVardef@b3659_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2021

Accumulation of lncRNAs/DNA hybrid reveals RNase HII transcripts down-regulation in psoriasis.

Long functional non-coding RNAs (lncRNAs) have been in the limelight in aging research because short telomeres are associated with higher levels of TERRA (Telomeric Repeat containing RNA). The genomic instability caused in Immune-mediated inflammatory diseases (IMID) especially in patients with psoriasis, which lead to short telomeres in psoriasis lesions, is a mechanism leading to cell aging. Research on the fraction of TERRA in hybrid with DNA offers avenues for new strategies. Skin samples were fractionated to obtain the RNA associated with DNA as a R-loop structure. TERRA analysis was performed by RT-qPCR and RNA-seq analysis. The higher amount of TERRA levels attached with each chromosome end was found with psoriasis patients. The increased levels of TERRA linked with telomeres correlate with the decrease in the RNase-HII transcript which means the unresolved DNA/RNA hybrids may ultimately facilitate the formation of skin lesions. LncRNAs have multiple molecular functions, including the regulation of heterochromatin, which controls genome stability and epigenome shaping and may be used as a trans-generational prognostic marker in patients with psoriasis.

molecular biology↗

bioRxiv2019

Shared Genetic Risk between Eating Disorder- and Substance-Use-Related Phenotypes: Evidence from Genome-Wide Association Studies

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder (MDD). Total sample sizes per phenotype ranged from ~2,400 to ~537,000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; q<0.0001), and cannabis initiation and AN with binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating (rgs=-0.19 to -0.23; qs<0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for MDD loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships between these behaviors.

genetics↗

bioRxiv2017

The Anorexia Nervosa Genetics Initiative: Overview and Methods

BackgroundGenetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13000 individuals with AN as well as ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research.\n\nMethodsANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H.\n\nResultsBlood samples and clinical information were collected from 13,364 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable.\n\nConclusionsOur multipronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.gov NCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

genetics↗

bioRxiv2017

Examination of the Shared Genetic Basis of Anorexia Nervosa and Obsessive-Compulsive Disorder

Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a crossdisorder GWAS meta-analysis of 3,495 AN cases, 2,688 OCD cases and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (rg = 0.49 {+/-} 0.13, p = 9.07x10-7) and a sizable SNP heritability (SNP h2 = 0.21 {+/-} 0.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., bipolar disorder, schizophrenia, neuroticism) and negative correlations with metabolic phenotypes (e.g., BMI, triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN/OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.

genetics↗

bioRxiv2016

Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability [Formula] of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.

genomics↗