Biology subjects

Rajendran, K.

Publications and source records attributed to Rajendran, K..

4 recordsLinked to original sources

bioRxiv2025

Epigenetic Context Defines the Transcriptional Activity of Canonical and Noncanonical NF-κB Signaling in Pancreatic Cancer

NF-{kappa}B signaling can be subdivided into canonical and noncanonical pathways, culminating in the transcriptional activity of RELA and RELB, respectively. However, the upstream signals that activate these transcription factors and their specific regulatory roles in pancreatic ductal adenocarcinoma (PDAC) remain incompletely understood. Here, we demonstrate that TNF is the primary activator of canonical NF-{kappa}B signaling via RELA, while TWEAK engages noncanonical signaling through RELB in PDAC. Using transcriptome-wide gene expression, genome-wide occupancy profiling, and epigenome mapping, we delineate distinct temporal dynamics and regulatory activities of each pathway. Single-cell RNA-seq analysis and multiplex immunofluorescence staining in primary PDAC samples further reveal extensive and distinct interactions with components of the tumor microenvironment. Motif analysis of RELA- and RELB-bound regions uncovers a particularly strong association of RELB with AP1 elements. Notably, while RELA binds to both open and closed chromatin, RELB exclusively occupies regions with pre-existing chromatin accessibility and AP1 co-binding. Collectively, these findings underscore the distinct and complementary roles of TNF and TWEAK in PDAC, with TNF engaging a broader transcriptional program via RELA and TWEAK selectively targeting genes marked by accessible chromatin and epigenetic activity. This study provides critical insights into the regulatory dynamics of NF-{kappa}B signaling in PDAC, highlighting unique and complementary functions of RELA and RELB in modulating downstream gene expression. SignificanceTNF and TWEAK selectively activate RELA and RELB in pancreatic cancer, revealing that RELB-driven noncanonical signaling depends on chromatin accessibility and AP-1, uncovering distinct, targetable epigenetic dependencies from canonical signaling. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=59 SRC="FIGDIR/small/661561v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@14aa356org.highwire.dtl.DTLVardef@1297741org.highwire.dtl.DTLVardef@1545741org.highwire.dtl.DTLVardef@2c982b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Neural mechanisms of attention, not expectation, govern spatial selection by probabilistic cueing

Spatial probabilistic "Posner" cueing is widely employed in studies of endogenous spatial attention. Such cueing guides attention by providing prior knowledge about the likely spatial location of task-relevant events. Yet, it has been compellingly argued that such spatial priors also elicit expectation effects, rendering Posner cueing unsuitable for measuring attentional effects in isolation. We address this debate by combining signal detection theory models of behavior with concurrent electrophysiological recordings, and directly compare Posner cueing effects with those of attention and expectation cueing. Participants performed two tasks: a dual cueing task, with orthogonal relevance (attention) and probability (expectation) cues, as well as a Posner cueing task. Relevance and probability cueing independently modulated distinct behavioral parameters - perceptual sensitivity and decisional criterion, respectively - whereas Posner cueing modulated both sensitivity and criterion. However, only sensitivity modulations by Posner cueing were correlated with those of relevance cueing. Criterion modulations by Posner cueing were uncorrelated with those of probability cueing. Both Posner and relevance cueing, but not probability cueing, modulated various neural markers of spatial attention, including steady-state visually evoked potential (SSVEP) amplitude and alpha-band (8-12 Hz) oscillation power. Representational similarity analysis and cue-label prediction with deep convolutional neural networks revealed dissociable underpinnings of relevance and probability cueing, and identified Posner cueings neural representations with those of relevance cueing. Our results address a long-standing debate in the attention literature and clearly demonstrate that spatial selection by probabilistic cueing is governed by neural mechanisms of attention, not expectation. Significance StatementHow does our brain select relevant information for accomplishing task goals? "Posner cueing" is a popular choice for studying brain mechanisms of goal-driven attention in the lab. Posner cues guide attention by providing advance information about the likely location of task-relevant events. Yet, Posner cueing has been criticized because it engages brain mechanisms not only of attention but of event expectation, as well. We address this critique by employing state-of-the-art neural decoding approaches, including deep convolutional neural networks, and show that behavioral and neural underpinnings of Posner cueing closely match those of attention, not expectation. The results address a long-standing debate in the attention literature and validate Posner cueing as a reliable method for measuring attentions effects in the brain.

neuroscience↗

bioRxiv2023

Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Neuronal activity drives global alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. Here we show that neuronal activity induces widespread transcriptional upregulation and downregulation in astrocytes, highlighted by the identification of a neuromodulator transporter Slc22a3 as an activity-inducible astrocyte gene regulating sensory processing in the olfactory bulb. Loss of astrocytic Slc22a3 reduces serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduces expression of GABA biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes, while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.

neuroscience↗

bioRxiv2017

Traction force screening enabled by compliant PDMS elastomers

Acto-myosin contractility is an essential element of many aspects of cellular biology, and manifests as traction forces that cells exert on their surroundings. The central role of these forces makes them a novel principal therapeutic target in diverse diseases. This requires accurate and higher capacity measurements of traction forces; however, existing methods are largely low throughput, limiting their utility in broader applications. To address this need, we employ Fourier-transform traction force microscopy in a parallelized 96-well format, which we refer to as contractile force screening (CFS).Critically, rather than the frequently employed hydrogel polyacrylamide (PAA), we fabricate these plates using polydimethylsiloxane (PDMS) rubber. Key to this approach is that the PDMS used is very compliant, with a lower-bound Youngs modulus of approximately 0.7 kPa. We subdivide these monolithic substrates spatially into biochemically independent wells, creating a uniform multiwell platform for traction force screening. We demonstrate the utility and versatility of this platform by quantifying the compound and dose-dependent contractility responses of human airway smooth muscle cells and retinal pigment epithelial cells.

biophysics↗