Biology subjects

Darieva, Z.

Publications and source records attributed to Darieva, Z..

4 recordsLinked to original sources

bioRxiv2024

The level of HAND1 controls the specification of multipotent cardiac and extraembryonic progenitors

Diverse sets of progenitors contribute to the development of the embryonic heart, but the mechanisms of their specification have remained elusive. Here, using a human pluripotent stem cell (hPSC) model, we deciphered cardiac and non-cardiac lineage trajectories in differentiation and identified transcription factors underpinning cell specification, identity and function. We discovered a concentration-dependent, fate determining function in mesodermal progenitors for the basic helix-loop-helix transcription factor HAND1 and uncovered its gene regulatory network. At low level, HAND1 directs differentiation towards multipotent juxta-cardiac field progenitors able to make cardiomyocytes and epicardial cells, whereas at high level it promotes the development of extraembryonic mesoderm. Importantly, HAND1-low progenitors can be propagated in their multipotent state. This detailed mechanistic insight into human development will accelerate the delivery of effective disease modelling, including for congenital heart disease, and cell therapy-based regenerative medicine.

developmental biology↗

bioRxiv2024

The evolutionary ancient MEIS transcription factors actuate lineage-specific transcription to establish cardiac fate

Control of gene expression is commonly mediated by distinct combinations of transcription factors (TFs). This cooperative action allows multiple biological signals to be integrated at specific regulatory elements, resulting in highly specific gene expression patterns in space and time. It is unclear whether combinatorial binding is also necessary to bring together TFs with distinct biochemical functions, which collaborate to effectively recruit and activate RNA polymerase II. Using a cardiac differentiation model, we find that the largely ubiquitous, evolutionary ancient homeodomain proteins MEIS are essential for activating a cardiac-specific gene expression program. MEIS TFs act as actuators, fully activating transcriptional programs selected by lineage-restricted TFs to drive the dynamic progression of cardiac differentiation. Combinatorial binding of MEIS with lineage-enriched TFs, GATA and HOX, provides selectivity, guiding MEIS to function at cardiac-specific enhancers. In turn, MEIS TFs promote accumulation of the methyltransferase KMT2D to initiate lineage-specific enhancer commissioning. MEIS combinatorial binding dynamics, dictated by the changing dosage of its partners, drive cells into progressive stages of cardiac differentiation. Our results uncover tissue-specific transcriptional activation as the result of ubiquitous actuator TFs harnessing general transcriptional coactivators at tissue-specific enhancers, to which they are directed by binding with lineage- and domain-specific TFs.

developmental biology↗

bioRxiv2022

Motif2Site: a Bioconductor package to detect accurate transcription factor binding sites from ChIP-seq

AO_SCPLOWBSTRACTC_SCPLOWTranscription factors (TFs) binding are in the core of the Regulatory networks studies. ChIP-seq experiments are available for many TFs in various species. As TFs co-bind in cis-regulatory elements regions to control gene expression, studying the existing relation among co-binding TFs such as distance of binding sites or co-occupancy are highly important to understand the regulatory mechanisms. Currently, to detect binding sites of each TF in cis-regulatory elements, first binding regions of each TF are detected by standard peak calling methods, and at the second step the best candidate binding sites are prioritized by motif detection methods in binding regions. However, it is well-known that the best prioritized candidate motifs are not necessarily the actual binding sites of TFs. Furthermore, motif prioritizing methods that consider more genomic features complexities of TFs bindings are usually computationally expensive methods. Here, we tend to improve the TF binding sites accuracy detection by using the original ChIP-seq signal. The motifs which are located closer to the summits of binding region peaks are more likely to be the actual binding sites. Therefore, We developed a novel post-processing Bioconductor package called Motif2Site to detect TFs binding sites from user provided motif sets and recenter them across experiments. We applied Motif2Site method to detect TF binding sites for major mouse embryonic stem cell (mESC) as well as mouse fetal and birth time (P0) heart TFs. Motif2Site could detect binding regions with comparable accuracy to the existing state-of-the-art while it substantially increased the accuracy of the detected binding sites. Motif2Site could future improve the accuracy of binding sites prediction by recentering binding sites across developmental conditions (fetal/P0 heart) and across homologous TFs (ex. GATA4/GATA6 and MEF2A/MEF2C). Purifying high-confidence binding sites in mouse fetal heart, enabled us to study the co-binding properties of TFs in cis-regulatory elements. We could also traced TFs footprints in selected heart-specific VISTA enhancers chromatin accessible regions.

bioinformatics↗

bioRxiv2019

SWR1 Chromatin Remodeling Complex Prevents Mitotic Slippage during Spindle Position Checkpoint Arrest

Faithful chromosome segregation in budding yeast requires correct positioning of the mitotic spindle along the mother to daughter cell polarity axis. When the anaphase spindle is not correctly positioned, a surveillance mechanism, named as the spindle position checkpoint (SPOC), prevents the progression out of mitosis until correct spindle positioning is achieved. How SPOC works on a molecular level is not well-understood. Here, we performed a genome-wide genetic screen to search for components required for SPOC. We identified the SWR1 chromatin-remodeling complex (SWR1-C) among the several novel factors that are essential for SPOC integrity. Cells lacking SWR1-C were able to activate SPOC upon spindle misorientation but underwent mitotic slippage upon prolonged SPOC arrest. This mitotic slippage required the Cdc14-early anaphase release pathway and other factors including the SAGA histone acetyltransferase complex, proteasome components, the mitotic cyclin-dependent kinase inhibitor Sic1 and the mitogen-activated protein kinase Slt2/Mpk1. Together, our data establish a novel link between chromatin remodeling and robust checkpoint arrest in late anaphase. AUTHORS SUMMARYBefore it physically divides into two, the cell must duplicate its genetic material and separate the duplicated copies to the opposite poles of the cell with the help of the spindle machinery. The direction along which the genetic material is separated has different consequences on cell division, especially when the opposite poles of the cell differ from each other, as is the case of asymmetric cell division. Every cell division in budding yeast is asymmetric. The new (daughter) cell grows on the old (mother) cell and pinches of from this location at the end of the cell division, giving rise to a new and an old cell. The daughter and mother cells differ in size and composition, thus the cell division is asymmetric. In order for the daughter cell to receive one copy of the duplicated genetic material, budding yeast has to separate the copies of its genetic material along the mother to daughter cell direction, which is possible by placing the spindle apparatus along this direction. A surveillance mechanism named the Spindle Position Checkpoint (SPOC) in budding yeast monitors the position of the mitotic spindle and prevents cells from dividing if the spindle fails to align in the mother to daughter direction. The cell can resume cell division only after correcting the position of the spindle followed by inactivation of SPOC. This way SPOC prevents multi-nucleation and enucleation, and hence it is a crucial mechanism to maintain the correct ploidy. It has been known that about five proteins play a role in positively supporting the SPOC. Yet, how SPOC works on a molecular level remains ill understood. In this study, we aimed to find out novel components of SPOC. Through an unbiased genome-wide genetic screen, we successfully identified several new components of the SPOC machinery. Among several other novel proteins identified, we investigated the role of the SWR1 chromatin remodeling complex (SWR1-C) in more detail. We show that the SWR1-C has a function in preventing cells with mis-positioned spindles from resuming cell division when the spindle stays mis-positioned for a prolonged time (mitotic slippage). Our data indicated that SWR1-C is not required to start the immediate SPOC response, rather it is important to keep the prolonged SPOC arrest.

cell biology↗