Biology subjects

Yildirim, E.

Publications and source records attributed to Yildirim, E..

5 recordsLinked to original sources

bioRxiv2023

Stress granule formation helps to mitigate neurodegeneration

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP (rin in Drosophila) and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.

neuroscience↗

bioRxiv2023

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice

Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle where it is best known for its role in store operated Ca2+ entry (SOCE). Genetic syndromes resulting from STIM1 mutations are recognized as a cause of muscle weakness and atrophy. Here, we focus on a gain of function mutation that occurs in humans and mice (STIM1+/D84G mice) where muscles exhibit constitutive SOCE. Unexpectedly, this constitutive SOCE did not affect global Ca2+ transients, SR Ca2+ content or excitation contraction coupling (ECC) and was therefore unlikely to underlie the reduced muscle mass and weakness observed in these mice. Instead, we demonstrate that the presence of D84G STIM1 in the nuclear envelope of STIM1+/D84G muscle disrupts nuclear-cytosolic coupling causing severe derangement in nuclear architecture, DNA damage, and altered lamina A associated gene expression. Functionally, we found D84G STIM1 reduced the transfer of Ca2+ from the cytosol to the nucleus in myoblasts resulting in a reduction of [Ca2+]N. Taken together, we propose a novel role for STIM1 in the nuclear envelope that links Ca2+ signaling to nuclear stability in skeletal muscle.

physiology↗

bioRxiv2022

period Translation as a Core Mechanism Controlling Temperature Compensation in an Animal Circadian Clock

The most enigmatic of the canonical properties of circadian clocks is temperature compensation where circadian period length is stable across a wide temperature range despite the temperature dependence of most biochemical reactions. While the core mechanisms of circadian clocks have been well described, the molecular mechanisms of temperature compensation are poorly understood especially in animals. A major gap is the lack of temperature compensation mutants that do not themselves unambiguously affect the temperature dependence of the encoded protein. Here we show that null alleles of two genes encoding components of a complex important for translation of the core clock component period in circadian pacemaker neurons robustly alter the temperature dependence of circadian behavioral period length. These changes are accompanied by parallel temperature dependent changes in oscillations of the PER protein and are consistent with the model that these translation factors mediate the temperature-dependence of PER translation. Consistent with findings from modeling studies, we find that translation of the key negative feedback factor PER plays an instrumental role in temperature compensation.

genetics↗

bioRxiv2022

Xist expression impacts chromatin structure and YY1 mediated transcription of X-linked genes in hematopoietic progenitor cells

X chromosome inactivation (XCI) is a dosage compensation phenomenon that occurs in females. Initiation of XCI depends on Xist RNA, which triggers silencing of one of the two X chromosomes, except for genes that escape XCI. This inactive state is propagated during cell divisions with continuous Xist expression. How Xist impacts XCI maintenance remains an open question. Here, we delete Xist in hematopoietic cells of mice and report increased fraction of cycling hematopoietic progenitors and differentiation defects during hematopoiesis. Xist loss results in upregulation of a subset of X-linked genes, several of which escape XCI and have functions in hematopoiesis and immunity. We find that the underlying mechanism of transcriptional upregulation involves reduced H3K27me3 occupancy and increased chromatin accessibility which accommodate binding of YY1 transcription factor (TF). We propose that XCI maintenance defects in Xist deficient mice rely on the landscape of open chromatin sites, TF availability, and cell cycle stress in specific cellular context during hematopoiesis.

cell biology↗

bioRxiv2020

Nucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding at cis-regulatory elements and TAD boundaries

The nuclear pore complex (NPC) components, nucleoporins (Nups), have been proposed to mediate spatial and temporal organization of chromatin during gene regulation. Nevertheless, we have little understanding on the molecular mechanisms that underlie Nup-mediated chromatin structure and transcription in mammals. Here, we show that Nucleoporin 153 (NUP153) interacts with the chromatin architectural proteins, CTCF and cohesin, and mediates their binding across cis-regulatory elements and TAD boundaries in mouse embryonic stem (ES) cells. NUP153 depletion results in altered CTCF and cohesin occupancy and differential gene expression. This function of NUP153 is most prevalent at the developmental genes that show bivalent chromatin state. To dissect the functional relevance of NUP153-mediated CTCF and cohesin binding during transcriptional activation or silencing, we utilized epidermal growth factor (EGF)-inducible immediate early genes (IEGs). We found that NUP153 binding at the cis-regulatory elements controls CTCF and cohesin binding and subsequent POL II pausing during the transcriptionally silent state. Furthermore, efficient and timely transcription initiation of IEGs relies on NUP153 and occurs around the nuclear periphery suggesting that NUP153 acts as an activator of IEG transcription. Collectively, these results uncover a key role for NUP153 in chromatin architecture and transcription by mediating CTCF and cohesin binding in mammalian cells. We propose that NUP153 links NPCs to chromatin architecture allowing developmental genes and IEGs that are poised to respond rapidly to developmental cues to be properly modulated.

cell biology↗