Biology subjects

Di Giorgio, E.

Publications and source records attributed to Di Giorgio, E..

6 recordsLinked to original sources

bioRxiv2026

Targeting the NuRD Component, CHD4, Impairs Foxp3+ Treg Cell Production and Function and Promotes Anti-Tumor Immunity

Little is known about why Foxp3 regulatory T (Treg) cells require at least three HDAC1/HDAC2-containing chromatin-remodeling complexes (NuRD, Sin3 and CoREST), or whether selective disruption of these complexes can be exploited to enhance antitumor immunity. Here, we investigated the role of chromodomain helicase DNA- binding protein 4 (CHD4), the ATP-dependent remodeling subunit of the NuRD complex, in Treg biology. Conditional deletion of Chd4 in Foxp3 Tregs resulted in severe systemic autoimmunity and early lethality, accompanied by reduced Foxp3 expression, impaired Treg suppressive function, and loss of Treg lineage stability. Transcriptomic analyses demonstrated that CHD4 deficiency closely phenocopied Hdac2 deletion, whereas quantitative proteomic analyses revealed that CHD4 assembles into highly conserved NuRD complexes in both Treg and conventional CD4 T cells. These findings indicate that the selective dependence of Tregs on CHD4 does not arise from the formation of lineage-specific protein complexes but rather from the unique epigenetic program maintained by CHD4-containing chromatin-remodeling complexes that is required for Treg differentiation and stability. Using a novel cellular target-engagement platform, we identified CH41, a potent small-molecule inhibitor of CHD4 that recapitulated the effects of genetic CHD4 ablation on Treg function. Pharmacological inhibition of CHD4 impaired intratumoral Treg accumulation and function and significantly inhibited the growth of lung and hepatocellular carcinomas in immunocompetent, but not immunodeficient, mice, without inducing systemic autoimmunity. Collectively, our findings identify CHD4 as a critical epigenetic regulator of Treg lineage stability and establish pharmacological targeting of the CHD4/NuRD axis as a promising strategy to selectively disrupt tumor-associated Tregs and enhance antitumor immunity.

cancer biology↗

bioRxiv2026

Recognition and Resolution of KRAS 5'UTR RNA G-Quadruplexes by hnRNPA1

The KRAS oncogene, central to cellular signaling via MAPK and PI3K-AKT pathways, is a notorious cancer driver frequently activated in pancreatic, colorectal, and lung carcinomas. Regulation of human KRAS oncogene expression is important due to its capital role in cell growth, proliferation, and survival. Misregulation of its expression contributes directly to the development and progression of multiple types of cancer. In previous studies, the role of G-quadruplexes elements in both the promoter and 5 UTR regions have shown to play important roles in KRAS expression, particularly when these G4s elements interact with regulatory protein hnRNPA1. In this study, we reveal that KRAS expression is also modulated at the post-transcriptional level through the formation of RNA G-quadruplexes (rG4s) situated at the 5 untranslated region (5UTR) of the mRNA. Biophysical and binding studies were carried out to probe the interaction. Through isothermal titration calorimetry (ITC), we quantified a strong binding affinity between the UP1 domain of hnRNPA1 and short-nucleotide RNA segments capable of adopting different G-quadruplex fold. The binding interaction is characterized by a favorable Gibbs free energy change in the range of {Delta}G {approx} -32 to -34 kJ/mol, suggesting a specific and energetically favorable association. One-dimensional and two-dimensional 1H-15N HSQC NMR spectroscopy revealed pronounced chemical shift changes in residues of both RNA recognition motifs (RRMs) of UP1, signifying direct contact with the rG4 structure.

biophysics↗

bioRxiv2020

Newborns' sensitivity to speed changes as a building block for animacy perception

The human visual system can discriminate between animate beings vs. inanimate objects on the basis of some kinematic cues, such as starting from rest and speed changes by self-propulsion. The ontogenetic origin of such capability is still under debate. Here we investigate for the first time whether newborns manifest an attentional bias toward objects that abruptly change their speed along a trajectory as contrasted with objects that move at a constant speed. To this end, we systematically manipulated the motion speed of two objects. An object that moves with a constant speed was contrasted with an object that suddenly increases (Experiment 1) or with one that suddenly decreases its speed (Experiment 2). When presented with a single speed change, newborns did not show any visual preference. However, newborns preferred an object that abruptly increases and then decreases its speed (Experiment 3), but they did not show any visual preference for the reverse sequence pattern (Experiment 4). Overall, results are discussed in line with the hypothesis of the existence of attentional biases in newborns that trigger their attention towards some visual cues of motion that characterized animate perception in adults.

neuroscience↗

bioRxiv2020

HDAC4 controls senescence and aging by safeguarding the epigenetic identity and ensuring the genomic integrity

The epigenome of senescent cells is characterized by a deep redistribution of H3K27 acetylation. H3K27 is target of class IIa Histone Deacetylases (HDAC4, 5, 7, 9) as part of large repressive complexes. We report here that, among class IIa HDACs, HDAC4 is post-transcriptionally downregulated during senescence and aging. HDAC4 knock-out (KO) triggers premature senescence as a result of two waves of biological events: the accumulation of replication stress (RS) and the expression of inflammatory genes. The latter is achieved directly, through the activation of enhancers (TEs) and super-enhancers (SEs) that are normally monitored by HDAC4, and indirectly, through the de-repression of repetitive elements of retroviral origin (ERVs). The accumulation of DNA damage and the activation of the inflammatory signature influence each other and integrate into a synergistic response required for senescence onset. Our work discloses the key role played by HDAC4 in maintaining epigenome identity and genome integrity.

cell biology↗

bioRxiv2018

A cortical route for face-like pattern processing in human newborns

Humans are endowed with an exceptional ability for detecting faces, a competence that in adults is supported by a set of face-specific cortical patches. Human newborns already shortly after birth preferentially orient to faces even when they are presented in the form of highly schematic geometrical patterns, over perceptually equivalent non-face-like stimuli. The neural substrates underlying this early preference are still largely unexplored. Is the adult face-specific cortical circuit already active at birth, or does its specialization develop slowly as a function of experience and/or maturation? We measured EEG responses in 1-4 days old awake, attentive human newborns to schematic face-like patterns and non-face-like control stimuli, visually presented with a slow oscillatory \"peekaboo\" dynamics (0.8 Hz) in a frequency-tagging design. Despite the limited duration of newborns attention, reliable frequency-tagged responses could be estimated for each stimulus from the peak of the EEG power spectrum at the stimulation frequency. Upright face-like stimuli elicited a significantly stronger frequency-tagged response than inverted face-like controls in a large set of electrodes. Source reconstruction of the underlying cortical activity revealed the recruitment of a partially right-lateralized network comprising lateral occipito-temporal and medial parietal areas largely overlapping with the adult face-processing circuit. This result suggests that the cortical route specialized in face processing is already functional at birth.\n\nSignificance statementNewborns show a remarkable ability to detect faces even minutes after birth, an ecologically fundamental skill that is instrumental for interacting with their conspecifics. What are the neural bases of this expertise? Using EEG and a slow oscillatory visual stimulation, we identified a reliable response specific to face-like patterns in newborns, which underlying cortical sources largely overlap with the adult face-specific cortical circuit. This suggests that the development of face perception in infants might rely on an early cortical route specialized in face processing already shortly after birth.

neuroscience↗

bioRxiv2017

A mental number line in human newborns

In the 19th century Francis Galton first reported that humans represent numbers on a mental number line with smaller numbers on the left and larger numbers on the right. It has been suggested that this orientation emerges as a result of reading/writing habits for both words or numbers. Recent evidence in animals and infants in the first months of life has challenged the primary role of language in determining the left-to-right direction of spatial-numerical association, SNA. However, the possibility that SNA is learnt by early exposure to caregivers directional biases is still open. Here we show that 55-hour-old newborns, once habituated to a number (i.e., 12), spontaneously associated a smaller number (i.e., 4) with the left side and a larger number (i.e., 36) with the right side of space. Moreover, SNA in neonates was not absolute but relative. The same number (i.e., 12) was associated with the left side whenever the previously experienced number was larger (i.e., 36), but with the right side whenever the number was smaller (i.e., 4). Control on continuous physical variables showed that the effect was specific of discrete magnitudes. Hence, soon after birth humans associate smaller numbers with the left space and larger numbers with the right space. These results constitute strong evidence that in our species SNA originates from pre-linguistic and biologically precursors in the brain.\n\nSIGNIFICANCE STATEMENTFor human adults, the representation of number and space is profoundly intertwined. Humans represent numbers on a left to right oriented Mental Number Line (MNL), with small numbers located on the left and larger ones on the right. How do these connections arise? Do we learn to associate numbers with space throughout cultural learning and social interactions or is this association rooted in the biology of the human brain? We showed that neonates spontaneously associate numbers with space. After being habituated to a certain number, neonates associated a smaller number with the left and a larger number with the right side. This evidence demonstrates that a predisposition to map numbers onto space is rooted in human neural systems.

neuroscience↗