Arginine residue side chains can be deiminated, whereby a terminal nitrogen atom is replaced with oxygen. Without changing the atoms in a proline residue, reversible isomerization can change its structure. In this way, the expression of genes can be altered in a cell or a cell lineage without changing the DNA sequence.Ĭertain residue side chains can undergo chemical modifications, (4) which expand the building blocks of proteins from the 20 canonical amino acids to a growing list of interesting molecules, and expand the proteome to include differentially modified proteins. Through these actions, chromatin structure can be altered during one’s lifetime in response to a variety of environmental and internal conditions. Yet these distinctions are not static: enzymes that modify DNA and histones, chaperones that allow histones to be replaced, and enzymes that consume ATP to slide nucleosomes can alter the local chromatin structure. For example, telomeres and centromeres are generally silenced, and boundary elements prevent the silencing from spreading into regions that are turned “on”. Open, permissive, active chromatin promotes DNA transcription and replication, whereas closed, silenced, repressed chromatin is turned “off” to these processes. The physical structure of chromatin has functional consequences for DNA templated processes, including gene expression, DNA replication, and DNA repair. By applying this methodology across a diverse collection of cell states and contexts, we put forth hypertranscription as a general and dynamic cellular program that is pervasively employed during development, organ maintenance and regeneration.Chromatin can be assembled in different conformations, which are influenced by a variety of factors, including DNA sequence elements, DNA modifications, histone modifications, incorporation of histone variants, nucleosome occupancy and spacing, nucleosome sliding, and association of nonhistone proteins with the chromatin. Our findings introduce an approach towards maximizing single-cell RNA-seq profiling. Our analyses reveal a common set of molecular pathways associated with hypertranscription across adult organs, including chromatin remodeling, DNA repair, ribosome biogenesis and translation. In addition to the association between hypertranscription and the stem/progenitor cell state, we dissect the relationship between transcriptional output and cell cycle, ploidy and secretory behavior. Hypertranscription marks cells with multilineage potential in adult organs, is redeployed in conditions of tissue injury, and can precede by 1-2 days bursts of proliferation during regeneration. We find that many different multipotent stem and progenitor cell populations are in a state of hypertranscription, including in the hematopoietic system, intestine and skin. The results reveal a remarkable dynamic range in transcriptional output among adult cell types. Absolute scaling enables an estimation of total transcript abundances per cell, which we validate in embryonic stem cell (ESC) and germline data and apply to adult mouse organs at steady-state or during regeneration. Here, we use molecule counting and spike-in normalization to develop absolute scaling of single-cell RNA sequencing data. This limitation is in large part due to the fact that modern sequencing approaches, including single-cell RNA sequencing (scRNA-seq), generally assume similar levels of transcriptional output per cell. Despite its potential widespread relevance, documented examples of hypertranscription remain few and limited predominantly to early development. Hypertranscription facilitates biosynthetically demanding cellular state transitions through global upregulation of the nascent transcriptome.
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