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LECTURE 19: RNA REGULATORY MECHANISMS. Levels of specific messenger RNAs can differ in different types of cells and at different times in the same cell. In prokaryotes, control of RNA abundance can be at the level of transcription initiation or transcription elongation (attenuation).

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slide1

LECTURE 19: RNA REGULATORY MECHANISMS

Levels of specific messenger RNAs can differ in different types of cells

and at different times in the same cell.

In prokaryotes, control of RNA abundance can be at the level of

transcription initiation or transcription elongation (attenuation).

In eukaryotes, RNA abundance is regulated by transcription initiation,

attenuation, splicing, or rate of RNA degradation.

Control of transcription initiation in eukaryotes is exerted in gene-specific

manner by sequence-specific DNA binding proteins and in a region- or

chromosome-wide manner by covalent modifications of DNA or chromatin.

slide2

Sequence Specific Homodimeric DNA Binding Proteins Bind DNA Palindromes

Protein sides chains often achieve binding specificity by hydrogen bonding

with base motifs within the DNA major groove.

slide4

Homeodomain-Containing Factors Contain Helix-Turn-Helix Motif

Heterodimerization provides greater target specificity by lengthening

recognition sequence.

slide6

Prokaryotic Regulation by Induction and Repression of Transcription Initiation

Lactose catabolism utilizes regulation at the LAC operon

slide7

Lac Operon Encodes Multiple Proteins Involved in Lactose Metabolism

Lac repressor is constitutively synthesized from the LacI gene

Repressor binds to operator (LacO) just downstream of operator promotor

and prevents operon transcription by blocking RNA polymerase movement

Lactose or non-hydrolizable analogs bind the repressor and prevent

its binding to LacO, thereby promoting operon transcription

slide8

Glucose Inhibits Lac Operon Transcription Initiation by Catabolite Repression

Efficient binding of RNA polymerase to the

Lac operon promoter (P) requires binding of

cAMP to CAP proteins.

cAMP accumulates only when ATP levels are

low. Glucose, the preferred energy source,

enables ATP synthesis and drop in cAMP

level, thereby inhibiting transcription

of the Lac operon

slide9

Prokaryotic Attenuation Enables Amino Acids to Inhibit Expression

of Amino Acid Biosynthetic Enzymes

TRP attenuator is preceding by short ORF with TRP codons

In absence of charged TRP tRNA, ribosome stalls at TRP codons and

prevents attenuator RNA region from adopting a stem-loop mediating

transcription termination (attenuation)

slide10

Eukaryotic DNA Is Compacted by Assembly Into Nucleosomes

Histone proteins H2A, H2B, H3, H4 have basic (+ charged) tails and

complex into a core octamer. DNA wraps around the core, stabilized by

electrostatic interaction between histone tails and

backbone phosphates along DNA chain.

Each nucleosome contains 140 bp DNA, with an

internucleosomal distance usually 40 bp.

Tight binding of DNA to histones in nucleosomes

inhibits access of transcription factors, repressing

transcription.

slide11

Histone Acetylation Helps Activate Chromatin

Acetylation of histone tails in nucleosomes weakens DNA binding to

histone cores, creating “open” chromatin competent for gene transcription.

Open chromatin is amenable to transcription factor binding to specific

sites on DNA (promoters/ enhancers)

Acetylated histones also directly recruit other proteins

containing bromodomains, some of which have

activator regions that help assemble transcription

machinery.

Non-acetylated chromatin leads to other modifications

(e.g., CpG DNA methylation) that stabilizes inactive state

slide12

X Chromosome Inactivation Is Mammalian Mechanism for Control of Gene Dosage

In most tissues, gene expression must be precisely controlled. X chromosome

presents a particular developmental challenge, since males have one X and

females have two X chromosomes. Problem solved by X inactivation.

slide13

Random X Inactivation Mediated by Xic, Xist, and Tsix

Random X chromosome inactivation mediated by interaction of X inactivation

centers (Xics) on two X chromosomes of female cells.

Xic interaction first triggers transcription of Xist and Tsix RNAs from each

X chromosome. Xist and Tsix are large RNAs without coding sequences.

Xist binds to the chromosome from which it was transcribed, and Tsix

probably prevents accidental binding to other X chromosome.

Xist RNA eventually “paints” the entire X chromosome from which it is

transcribed, causing inactivation …. By this point, the only gene

transcribed from the inactivated chromosome is Xist.

Meanwhile, Tsix paints the active X chromosome, preventing spread of

inactivation to the second chromosome.

slide14

Mechanism of Xist-Mediated X Inactivation Still Uncertain

Xist RNA recruits novel proteins to inactivating X chromosome, induces

methylation of histone tails, and bears a 5’ end essential for gene

silencing.

After induction of X-inactivation, Xist is no longer required for its maintenance.

slide15

Some Eukaryotic Transcription Factors Are Master Regulators of Differentiation

Myogenin and MyoD are bHLH transcription factors that drive differentiation

of skeletal muscle. All genes encoding proteins specific for muscle have

enhancers that recruit Myogenin and MyoD.

Ectopic expression of Myogenin or MyoD in fibroblasts converts them to

muscle cells.

Homeotic proteins contain DNA-binding homeodomains. The repertoire

of homeotic proteins expressed in a region of developing embryo

determines which kind of body part will form from that tissue.

Homeotic proteins do not specify particular differentiated cell types, but

determine the shapes of developing tissue regions.

slide18

Nuclear Hormone Receptors Classified Into Two Subgroups

Based Upon Behavior of Receptor in Absence of Hormone

(Subgroup 1)

One subclass of nuclear receptors includes glucocorticoid, estrogen,

and progesterone receptors.

In absence of hormone, the hormone-binding domain interacts with

Hsp90 (a heat shock protein)

Binding of Hsp90 prevents the receptor from docking to its DNA

recognition site. Mechanism is probably a steric obstruction by the

large Hsp90 protein

Hormone must have greater affinity for receptor than does Hsp90,

thereby displacing Hsp90 and allowing for DNA binding along

with co-activator recruitment.

slide19

Nuclear Hormone Receptors Classified Into Two Subgroups

Based Upon Behavior of Receptor in Absence of Hormone

(Subgroup 2)

Second subclass of receptors includes those for thyroid hormone,

retinoic acid, and vitamin D.

In absence of hormone, these receptors do not bind Hsp90 and still

associate with their sequence-specific DNA binding sites.

Without hormone, docked receptors cannot recruit co-activators.

Unliganded receptors, in fact, recruit repressor proteins or protein

complexes, including histone deacetylases (HDACs), which render

regional chromatin inactive through removal of histone acetylations.

Gene expression regulated by these receptors is under very tight control,

mediating both repression and activation of transcription.