Biology subjects

Hochedlinger, K.

Publications and source records attributed to Hochedlinger, K..

5 recordsLinked to original sources

bioRxiv2025

Hematopoietic stem cells undergo bidirectional fate transitions in vivo.

Differentiation of haematopoietic stem and progenitor cells (HSPCs) is widely considered unidirectional in vivo. Here, we developed clonal phylogenetic tracing (CP-tracer) by sequential genetic barcoding, which enabled high-resolution analysis of 181,695 subclones derived from 847 individually labelled HSPCs. This approach uncovered bidirectional fate transitions between myeloid-biased (My-) and lineage-balanced haematopoietic stem cells (HSCs). Individual HSC clones, distinguished by temporally unique serial barcodes, exhibited durable lineage bidirectionality, with dynamics favouring progressive accumulation of My-HSCs over time. CRISPR-Cas9 screening identified the homeobox gene Hhex as a suppressor of myeloid differentiation that enables pivoting toward balanced output. Hhex function is age-dependent, with its expression declining in aged HSCs. Together, these findings demonstrate unexpected plasticity in HSC differentiation, modulated in part by Hhex-mediated repression, that shifts over time to drive the myeloid bias characteristic of ageing.

cell biology↗

bioRxiv2021

Chromatin state barriers enforce an irreversible mammalian cell fate decision

Stem and progenitor cells have the capacity to balance self-renewal and differentiation. Hematopoietic myeloid progenitors replenish more than 25 billion terminally differentiated neutrophils every day under homeostatic conditions and can increase this output in response to stress or infection. At what point along the spectrum of maturation do progenitors lose capacity for self-renewal and become irreversibly committed to differentiation? Using a system of conditional myeloid development that can be toggled between self-renewal and differentiation, we interrogated determinants of this point of no return in differentiation commitment. Irreversible commitment is due primarily to loss of open regulatory site access and disruption of a positive feedback transcription factor activation loop. Restoration of the transcription factor feedback loop extends the window of cell plasticity and alters the point of no return. These findings demonstrate how the chromatin state enforces and perpetuates cell fate and identifies potential avenues for manipulating cell identity. HighlightsO_LIThere exists a point of irreversible commitment in granulocytic differentiation C_LIO_LIChromatin state dynamics establish the transition from self-renewal to differentiation commitment C_LIO_LIReduced chromatin accessibility underlies an irreversible loss of regulatory site access C_LIO_LIRestoration of a transcription factor feedback loop alters the differentiation commitment point C_LI

molecular biology↗

bioRxiv2020

The Histone Chaperone CAF-1 Sustains Myeloid Lineage Identity

During hematopoiesis, stem and progenitor cells become progressively restricted in their differentiation potential. This process is driven by lineage-specific transcription factors and is accompanied by dynamic changes in chromatin structure. The chromatin assembly factor complex CAF-1 is a key regulator of cellular plasticity in various cell lineages in different organisms. However, whether CAF-1 sustains lineage identity during normal homeostasis is unclear. To address this question, we investigated the role of CAF-1 in myeloid progenitor cells. CAF-1 suppression in myeloid progenitors triggered their rapid commitment but incomplete differentiation toward granulocyte, megakaryocyte, and erythrocyte lineages, resulting in a mixed cellular state. Through comparison with a canonical paradigm of directed terminal myeloid differentiation, we define changes in chromatin accessibility that underlie a unique transcriptome of the aberrantly matured CAF-1 deficient cells. We further identify C/EBP and ELF1 as key transcription factors whose control of myeloid lineage commitment is kept in check by CAF-1. These findings shed new light on molecular underpinnings of hematopoiesis and suggest that manipulation of chromatin accessibility through modulating CAF-1 levels may provide a powerful strategy for controlled differentiation of blood cells.

molecular biology↗

bioRxiv2019

Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1-3. Changes to DNA methylation patterns over time form the basis of an ageing clock4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns dont just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

molecular biology↗

bioRxiv2017

Reconstruction of developmental landscapes by optimal-transport analysis of single-cell gene expression sheds light on cellular reprogramming.

Understanding the molecular programs that guide cellular differentiation during development is a major goal of modern biology. Here, we introduce an approach, WADDINGTON-OT, based on the mathematics of optimal transport, for inferring developmental landscapes, probabilistic cellular fates and dynamic trajectories from large-scale single-cell RNA-seq (scRNA-seq) data collected along a time course. We demonstrate the power of WADDINGTON-OT by applying the approach to study 65,781 scRNA-seq profiles collected at 10 time points over 16 days during reprogramming of fibroblasts to iPSCs. We construct a high-resolution map of reprogramming that rediscovers known features; uncovers new alternative cell fates including neuraland placental-like cells; predicts the origin and fate of any cell class; highlights senescent-like cells that may support reprogramming through paracrine signaling; and implicates regulatory models in particular trajectories. Of these findings, we highlight Obox6, which we experimentally show enhances reprogramming efficiency. Our approach provides a general framework for investigating cellular differentiation.

bioinformatics↗