Evolution As It Was Meant To Be
A work in progress by
Stephen L. Talbott

Supplement C

Gene Regulation: A Partial Outline

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This is a preliminary draft of one chapter of a book-in-progress tentatively entitled, “Evolution As It Was Meant To Be — And the Living Narratives That Tell Its Story”. You will find here a fairly lengthy article serving as a kind of extended abstract of major parts of the book. This material is part of the Biology Worthy of Life Project. Copyright 2017-2019 The Nature Institute. All rights reserved. Publication: July 27, 2019. Last revision: July 27, 2019.

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“The remarkable complexity of gene regulation becomes increasingly apparent in proportion to the improving resolution of the available assays” (Kalsotra and Cooper 2011).

Following is the bare outline of a rather massive collection of notes I have haphazardly collected during the past decade from the technical literature on gene regulation. That collection is available under the title How the Organism Decides What to Make of Its Genes.

So why supply in this book the mere outline — the headings — under which those notes were collected? The main reason is that it gives the reader at least a vague sense for the remarkable variety of means (more than 250 major topics are listed below) by which the cell and organism decisively determine how their genes shall be used. Here I have in mind not only the general reader (who deserves to be spared all the technical details), but also the molecular biologist and geneticist. For I have found, rather to my surprise, that even these latter tend to be so narrowly focused on their own specialities that they have no clear idea of the full breadth of gene regulatory activity.

I hope, over time, to continue adding the kind of brief annotations you will find mostly associated with the earlier items in the outline. (You can read the annotations by clicking on the +/- symbols) The only other thing to add is that there are various caveats in connection with this document, such as the fact that the placement of some items under their higher-level headings doesn’t always make good sense — and, in any case, many items belong under more than one heading. As the original document grew and the shape of the research disciplines (and my own understanding) changed, it became too unwieldy to reorganize all the notes. The main lesson nevertheless emerges loud and clear.

You will find the various other caveats at the link given above. Quotations in the text below are from literature excerpts in the collection of notes, and are not attributed here.

A special tip: much of the technical language found here can easily be looked up in the glossary, which you may want to keep open in a separate window as you browse the descriptions below.

Negotiations among Parents and Offspring

Maternal RNA (+/-)

During the very earliest (and foundational) phase of embryonic growth, none of the RNA is produced by the embryo, but rather is inherited from the parents — mostly the mother, but some also from the father. Likewise, all the protein inherited or produced during this phase is derived from parental RNA.

Paternal RNA (+/-)

Contrary to expectation, what is inherited through the father’s gamete — quite apart from the genes — is now being found to have significance for the offspring.

Parentally modulated DNA methylation, histone modification, and other epigenetic effects (+/-)

The multifaceted processes through which histones are modified and DNA methylation is established or removed in egg and sperm have great effects upon the life of the new organism — and sometimes upon its further descendants.

X chromosome inactivation (+/-)

Cells in females must largely (but not completely!) inactivate one of the two X chromosomes, while overseeing many subtle changes in use of that chromosome.

Imprinting (+/-)

Parental gametes play a role in determining a modest but crucially important subset of genes in offspring that will be more or less silenced on one of the two chromosomes on which that gene occurs, based on whether the chromosome is maternally or paternally inherited. These changes are dynamically established and changed at various points in the life cycle.

Pre-Transcriptional Decision-Making

Promoters (+/-)

Promoters are stretches of regulatory DNA generally upstream from, and close to, the genes they regulate. The cell responds to these loci so subtly and with such nearly infinite diversity — for example, by means of DNA-binding proteins and histone-modifying activities — that, if we were to do reasonable justice to the regulatory variations, we would require an outline for promoters at least as long as the entirety of this current outline.

A few generalities (+/-)

Promoter sequences display countless variations, both in themselves and in their significant context. Transcription often can proceed either upstream or downstream from the promoter; a promoter can be found not only immediately upstream from a gene, but also inside a gene or at some remove from it; the regulatory use a cell makes of a promoter can be shaped not only by its DNA sequence, but also by the presence or absence of nucleosomes, modifications of both the DNA and histones, factors that re-position nucleosomes, and long-range interactions between the promoter and other regulatory elements such as enhancers. Promoters are no longer thought to rigidly specify anything; there are no absolute rules, and context, in all its plasticity, is everything.

Retrotransposons as promoters (+/-)

Large numbers of retrotransposons (“jumping gene” DNA sequences), once dismissed as parasitic DNA, are now known to function as alternative promoters and many of them give rise to alternative transcription start sites for protein-coding genes, or else produce non-protein-coding transcripts. “Retrotransposon transcription has a key influence upon the transcriptional output of the mammalian genome.”

Promoter activation kinetics (+/-)

Promoters may be slower or faster to respond to binding by a given transcription factor, and many transcription factors (and signaling processes in general) exhibit time-dependent behavior. And so the different dynamics elicit different expression patterns from different genes. Many factors may be involved. For example, “chromatin remodeling occurred more quickly at fast promoters”.

Dynamics of RNA polymerase II (+/-)

The behavior of RNA polymerase at the promoter — for example, it’s being paused there as opposed to quickly moving into elongation phase — has effects upon gene expression. “Abortive initiation may be viewed as promoter proofreading, and the structural transitions as checkpoints for promoter control”.

Pre-initiation complex
Tata-binding protein (TBP)
General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH)
Mediator complex
Transcription factors (other than general transcription factors)
DNA- and RNA-binding proteins
CpG islands
Co-activators and co-repressors
Enhancers and silencers
Exons and introns
Other DNA regulatory elements
DNA methylation
DNA 5-hydroxymethylation
Nucleosome positioning
Histone displacement and replacement during elongation
Nucleosome remodeling
Histone tail modifications
General considerations
Some particular modifications
Ubiquitination (or "ubiquitylation")
Some further general considerations
Relation to DNA replication and development
DNA methylation versus histone modifications
Core histones and their modifications
Histone variants
Histone H3 variants
Histone variant H2A.Z
Seasonal response of histone variants
Histone variants at the transcription start site
Acidic patch of the nucleosome core particle
Histone turnover
Nucleosome wrapping and unwrapping
Nucleosome structural plasticity, asymmetry, and conformational shifts
Linker histones (H1 histones)
Linker histone variants and modifications
Linker histones and integrated regulation
Chromatin structure and dynamics (including condensation and decondensation)
Chromatin condensation and decondensation
Histone chaperones
Chromatin remodeling proteins
Polycomb repressor complexes (PRC1 and PRC2)
ATP-dependent chromatin remodeling enzymes
Chromatin breathing
Chromatin-associated RNAs
DNA methylation
Epigenetic crosstalk
Splice sites
Cell signaling
Allele-specific expression
X chromosome inactivation
Autosomal monoallelic expression (MAE)
Allele-specific DNA methylation
Allele-specific histone modifications
Cis-regulatory polymorphism
Random allelic bias
Synonymous codons, codon usage, and tRNA abundances
Extrachromosomal DNA
Mitochondrial and viral DNA
DNA microdeletions and circular DNA
Small interfering RNAs (siRNAs)
MicroRNAs (miRNAs)
Metabolites and metabolic enzymes
Small peptides
Heavy metal ions
Hyperedited double-stranded RNAs

Decision-Making during Transcription

RNA polymerase
RNA polymerase pausing, release, and elongation
Alternative coding sequences (transcription start and termination)
Overlapping and interleaved transcription
Post-translational modifications of RNA Polymerase
Chromosome looping
RNA polymerase and alternative splicing
Transcription and formation of G-quadruplexes
5’-end cap, and cap-binding proteins
Histone modifications
Transcription of noncoding RNAs
Riboswitches and regulatory 5’ untranslated regions (5’UTRs)
RNA folding

Post-Transcriptional Decision-Making

Creation of mRNA variants
RNA splicing
Alternative splicing
Microexon splicing
tRNA splicing
Role of the minor spliceosome
Role of nuclear organization
Role of RNA polymerase
Role of RNA secondary and tertiary structure
Role of temperature
Role of histone modifications and chromatin structure
Role of mitochondria
Regulation and integration of the regulators
Exon shuffling
Circular RNAs

Detained introns
Stable intronic sequence RNAs (sisRNAs)
RNA editing
A-to-I editing
APOBEC1 (C-to-U) editing
RNA modifications

mRNA adenosine methylation (m6A and m1A)

“the deposition of m6A to mRNA species regulates most aspects of RNA processing, including transcript stability, pre-mRNA splicing, polyadenylation, mRNA export and translation.”

mRNA adenosine methylation (m6Am)
mRNA guanosine methylation
mRNA cytosine methylation
mRNA cytosine hydroxymethylation
mRNA cytidine acetylation

tRNA and rRNA modifications

“A human tRNA molecule [typically about 76 nucleotides long], on average, contains 11–13 different modifications. Accordingly, a large number of enzymes are involved in the site-specific deposition of the modifications”. The most abundant type of RNA is ribosomal RNA (rRNA), which is estimated to undergo about 130 different kinds of modification, most of which “occur in or close to functionally important sites and can facilitate efficient and accurate protein synthesis when they occur”.

Alternative cleavage, polyadenylation, and deadenylation
RNA 3’-end oligouridylation
Transcript leaders (5’-untranslated regions, or 5’-UTRs)
RNA cleavage
Nuclear export and RNA localization
RNA-protein complexes (RNPs)
Small nuclear ribonucleoproteins (snRNPs)
Exon junction complexes
RNA-binding proteins and RNA helicases
mRNA coordinators
mRNA -> mRNA regulation
Competing endogenous RNAs
Proteins that bind both DNA and RNA
RNA granules
Drosha-mediated mRNA cleavage
RNA degradation
RNA decapping
RNA polyadenylation and deadenylation
RNA polyuridylation
Decay of mRNAs containing AU-rich elements (AREs)
Nuclear receptors and mRNA decay
Decay of mRNAs containing GU-rich elements (GREs)
Nonsense-mediated mRNA decay (NMD)
Regulation of nonsense-mediated mRNA decay
No-go mRNA decay
Non-stop mRNA decay
Promoter-mediated RNA degradation
Alternatively spliced RNAs
Degradation by microRNAs and siRNAs
Antisense RNAs
Glucocorticoid receptor-mediated RNA decay
Staufen1-mediated RNA decay
Intron retention
Factors supporting both decay and transcription
Codon optimality
Co-translational mRNA decay
Supporting roles

Decision-Making Relating to Translation

Translation initiation
Translation speed and pausing
Role of the ribosome itselhromatin::Dynamics
Translational recoding
Mitochondrial ribosomal protein binding to cytoplasmic ribosomes
RNA sequence
Small open reading frames and upstream open reading frames (uORF)
Internal ribosome entry sites (IRESs)
Codon usage
RNA structure
Temperature-controlled translation
Transfer RNA (tRNA)
RNA-binding proteins
Staufen1 (Stau1) protein
Disordered protein as regulator of translation
mRNA localization
Targeting translation elongation
Alternative translation start sites
Alternative translation termination
Translational bypassing
Endoplasmic reticulum as regulator of translation
Stress granules and processing bodies as regulators of translation
Cytoskeleton as regulator of translation
Regulated “error” rates in protein synthesis
Nuclear sequestration of mRNAs

Post-Translational Decision-Making

Histone and histone tail modifications
Alternative protein folding
Protein homeostasis network
Post-translational modification of regulatory proteins
Methylation of arginine residues

Noncoding RNA

Noncoding RNA in general
MicroRNA (miRNA) activity
miRNAs can enhance gene expression
Role of Argonaute proteins
Role of other proteins
microRNAs are themselves subject to extensive regulation
Role of intercellular and exogenous microRNAs
Role of microRNA precursors
Small interfering RNAs (siRNAs)
Piwi-interacting RNAs (piRNAs)
Small intronic transposable element RNAs (siteRNAs)
Stable Intronic Sequence RNAs (sisRNAs)
Long noncoding RNAs
Regulation of transcription initiation
Allele-specific roles
Role in epigenetic regulation
Enhancer-like functions
Co- and post-transcriptional regulation by lncRNAs
Interaction with proteins
Interaction with other noncoding RNAs
Role in nuclear organization
Cytoplasmic functions
Role in genomic stability
Partial translation of long noncoding RNAs
Role in development and disease
Promoter-associated RNAs
Transcription initiation RNAs (tiRNAs)
tRNA-derived small RNAs (tsRNAs)
Enhancer RNAs
Antisense RNAs
5’ and 3’ untranslated regions
Other noncoding RNA roles
Caveat regarding “coding” and “noncoding” RNA

Repetitive and Transposable DNA

Transposable elements (transposons)
Retrotransposons in the germline
Some types of retrotransposon
LINE (long interspersed repeat element) retrotransposons
SINE (short interspersed repeat element) retrotransposons
LTRs (long terminal repeats)
Tandem repeats

Three-Dimensional Organization of Chromosomes, Nucleus, and Cell

Chromosome looping and long-distance chromatin interaction
Chromosome domains
Chromosome territories
Radial positioning of chromosome segments
Colocalization of genes (and "transcription factories")
Chromosomal rearrangements
Nuclear matrix
Nuclear envelope
Lamins and lamin-binding proteins
Cytoskeleton-DNA bridges
Nuclear pore complexes
Cell surface
Cell adhesion
Cell shape, extracellular matrix, and environment in general
Structural proteins
Insulator protein CTCF (CCCTC-binding factor)
Structural role of RNA

Other Aspects of the Molecular Structure and Dynamics of DNA and RNA

Conformational changes in general
DNA grooves: compression and decompression
DNA stretching on the nucleosome
Hoogsteen base pairing
Base pair opening
Bendability of double helix
Transient DNA strand separation (breathing)
Electrical structure of DNA
DNA-RNA duplexes (triplexes)
Double-stranded RNAs
DNA R-loops
DNA damage repair
DNA G-quadruplexes
RNA structure and dynamics
Stem loops and other secondary structures
RNA G-quadruplexes
Single-nucleotide “bulges”
Transient, dynamic conformation changes
Summary (mRNA only)

Miscellaneous (and Fundamental!)

Bioelectric effects
Mechanical effects
Phase transitions and membraneless organelles
Ribonucleoprotein phase transitions
Structured water
Genome remodeling
Aneuploidy and CNVs in the brain
Embryonic development
Polyploidy and aneuploidy in general
Somatic mitochondrial DNA (mtDNA) mutations
Genetic compensation
Extracellular genomic DNA fragments
Extracellular mRNA and miRNA
Physiology of the cell
Cell-to-cell variability

Integration of Gene Regulatory (and Other Cellular) Processes — A Very Few Examples

Example: Coupling of transcription and mRNA degradation
Example: Relation between transcription factor binding, chromatin modifications, and DNA methylation
Example: Some factors involved in heart development
Example: Antisense transcription, RNA splicing, noncoding RNA, and intronic promoter
Example: Vascular endothelial growth factor
Example: Nuclear receptor, structural protein, transcription factors, histone variant, and nucleosome positioning
Example: Interactions among neighboring genes, promoters, enhancers, splice sites, long noncoding RNAs, and transcription
Example: Aspects of chromatin organization
RNA splicing and RNA editing
DNA replication and transcription
Transcription factors, co-factors, and enhancers
Signaling pathways
Stem cells
Chromatin structure
The ribonome
Membrane architecture of the cell


Steve Talbott :: Gene Regulation: A Partial Outline