The Mediator complex and transcription regulation

Figures & data

Figure 1. Evolutionary timeline. Note large intervals for evolution of microbial to eukaryotic life, and for single-celled eukaryotes to metazoans. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Table 1. Basic comparison of Mediator subunits in humans (Hs), yeast (Sc), fly (Dm), and mouse (Mm) by percent identity, percent similarity, and size.

	Percent Identity to Hs			No. of Residues				Predicted MW (kDa)				Percent Similarity to Hs
Hs MED subunit	Sc	Dm	Mm	Hs	Sc	Dm	Mm	Hs	Sc	Dm	Mm	Sc	Dm	Mm
MED1	7%	24%	94%	1581	566	1475	1575	168.5	64.3	149.5	167.1	12%	38%	97%
MED4	21%	40%	94%	270	284	258	270	29.7	32.2	28.3	29.8	38%	58%	97%
MED6	19%	45%	95%	246	295	249	246	28.4	32.8	28.4	28.4	31%	63%	98%
MED7 (2)	23%	50%	97%	233	222	220	233	27.2	25.6	25.7	27.2	40%	66%	98%
MED8	15%	44%	97%	268	223	252	268	29.1	25.3	27.9	29.2	28%	60%	97%
MED9	16%	26%	78%	146	149	144	142	16.4	17.4	16.8	15.7	30%	46%	86%
MED10	24%	57%	99%	135	157	133	135	15.7	17.9	15.7	15.7	41%	75%	100%
MED11	19%	27%	97%	117	115	176	117	13.1	13.3	19.6	13.1	36%	42%	98%
MED14	13%	37%	96%	1454	1082	1553	1459	160.6	123.4	172.3	161.0	23%	53%	98%
MED15 (2)	18%	30%	89%	788	1081	749	792	86.8	120.3	80.5	87.1	27%	41%	92%
MED16 (4)	15%	27%	87%	877	974	818	828	96.8	111.3	90.0	91.8	27%	42%	90%
MED17	14%	43%	96%	651	687	642	649	72.9	78.5	71.6	72.6	27%	62%	98%
MED18	12%	47%	99%	208	307	217	208	23.7	34.3	24.7	23.6	24%	65%	100%
MED19	13%	29%	94%	244	220	337	244	26.3	24.9	35.4	26.3	22%	37%	96%
MED20	11%	36%	97%	212	210	252	212	23.2	22.9	27.9	23.2	19%	54%	99%
MED21	25%	54%	98%	144	140	142	144	15.6	16.1	16.1	15.6	42%	66%	99%
MED22	11%	43%	95%	200	121	143	200	22.2	13.9	16.6	22.3	22%	55%	96%
MED23 (4)	n/a	45%	96%	1368	n/a	1439	1367	156.5	n/a	167.1	156.1	n/a	63%	99%
MED24^a	15%	28%	94%	989	1132	993	987	110.3	128.8	111.7	110.0	29%	49%	97%
MED25 (4)	n/a	27%	93%	747	n/a	863	745	78.2	n/a	96.6	78.1	n/a	39%	94%
MED26	n/a	10%	85%	600	n/a	1483	588	65.4	n/a	165.5	64.7	n/a	16%	89%
MED27^a	13%	37%	98%	311	397	293	311	35.4	43.1	33.9	35.3	25%	60%	100%
MED28	n/a	24%	94%	178	n/a	189	178	19.5	n/a	21.1	19.5	n/a	37%	98%
MED29^a	8%	32%	92%	200	431	188	199	21.1	47.7	21.1	21.0	15%	45%	95%
MED30	n/a	20%	95%	178	n/a	318	178	20.3	n/a	35.3	20.4	n/a	31%	98%
MED31	28%	43%	98%	131	127	204	131	15.8	14.7	23.5	15.8	40%	55%	100%
CDK8	29%	71%	99%	464	555	454	464	53.3	62.8	53.7	53.2	38%	77%	99%
CDK19	n/a	n/a	96%	502	n/a	n/a	501	56.8	n/a	n/a	56.6	n/a	n/a	97%
CCNC	25%	68%	99%	283	323	267	283	33.2	37.8	31.3	33.2	40%	80%	100%
MED12	13%	34%	97%	2177	1427	2531	2190	243.1	166.9	279.5	244.6	24%	46%	98%
MED12L (2)	n/a	n/a	94%	2145	n/a	n/a	2157	240.1	n/a	n/a	241.4	n/a	n/a	96%
MED13 (3)	13%	27%	94%	2174	1420	2618	2171	239.3	160.0	280.0	238.6	22%	40%	97%
MED13L	n/a	n/a	92%	2210	n/a	n/a	2207	242.6	n/a	n/a	241.8	n/a	n/a	96%

Numbers in parentheses next to Mediator subunits represent the number of isoforms documented in Universal Protein Resource (UniProt). The superscript (^a) denotes that Hs subunits MED24, MED27 and MED29 were identified as orthologous to Sc MED5, MED3 and MED2 (Bourbon, 2008). All protein sequences were retrieved from UniProt, and percent identity and similarity were calculated using the EMBOSS Needle pairwise alignment tool on the EBI-EMBL server.

Table 2. List of human Mediator subunits, along with their approximate molecular weight.

Mediator subunit	Molecular weight
MED1	220 kDa
MED4	36 kDa
MED6	33 kDa
MED7	34 kDa
MED8	32 kDa
MED9	16 kDa
MED10	16 kDa
MED11	13 kDa
MED14	150 kDa
MED15	105 kDa
MED16	95 kDa
MED17	78 kDa
MED18	28 kDa
MED19	26 kDa
MED20	23 kDa
MED21	19 kDa
MED22	16 kDa
MED23	130 kDa
MED24	100 kDa
MED25	92 kDa
MED26	70 kDa
MED27	37 kDa
MED28	20 kDa
MED29	24 kDa
MED30	25 kDa
MED31	18 kDa
CDK8	55 kDa
CCNC	34 kDa
MED12	240 kDa
MED13	250 kDa

CDK8 module subunits are shown at the bottom.

Figure 2. EM structure of human Mediator compared with human Mediator lacking the MED1 and MED26 subunits. Both complexes are bound to the activation domain of VP16, and each is rendered at their predicted molecular weight (1.2 MDa or 0.9 MDa, respectively). The circled region indicates one area of missing protein density in the complex lacking MED1 and MED26. Note, however, that a pol II interaction surface (dashed yellow line; see text) is maintained in both structures, consistent with a general ability of each complex to activate transcription by VP16 (Taatjes & Tjian, 2004). (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Table 3. DNA-binding TFs and their identified Mediator subunit target(s)*.

Gene	TF	Reference	Organism	Gene	TF	Reference	Organism
MED1	TRα	Fondell et al., 1996		MED15	Smad2/4	Kato et al., 2002
		Yuan et al., 1998			Smad3/4	Kato et al., 2002
		Malik et al., 2004			NHR-49	Taubert et al., 2006	C. elegans
	TRβ	Yuan et al., 1998			Oaf1	Thakur et al., 2009	Yeast
		Zhu et al., 1997			Pdr1	Thakur et al., 2008	Yeast
	VDR	Yuan et al., 1998			Pdr3	Thakur et al., 2008	Yeast
		Rachez et al., 1999			VP16	Park et al., 2000	Yeast
	RARα	Yuan et al., 1998			Gal4	Park et al., 2000	Yeast
		Zhu et al., 1997			Gcn4	Park et al., 2000	Yeast
		Shao et al., 2000				Swanson et al., 2003	Yeast
		Lee et al., 2007				Zhang et al., 2004
	RXRα	Yuan et al., 1998			SREBP-1a	Yang et al., 2006
		Zhu et al., 1997		MED16	Dif	Kim et al., 2004
	PPARα	Yuan et al., 1998			Gcn4	Swanson et al., 2003	Yeast
		Zhu et al., 1997		MED17	VP16	Ito et al., 1999
	PPARγ	Yuan et al., 1998				Park et al., 2003	Drosophila
		Ge et al., 2002			p53	Ito et al., 1999
		Ge et al., 2008				Meyer et al., 2010
	ER	Kang et al., 2002			ER	Burakov et al., 2000
		Zhang et al., 2005			Hsf	Park et al., 2001b	Drosophila
		Burakov et al., 2000				Park et al., 2003	Drosophila
		Kim et al., 2008				Kim et al., 2004
		Warnmark et al., 2001			Dif	Park et al., 2003	Drosophila
	AR	Wang et al., 2002				Kim et al., 2004
	GR	Hittelman et al., 1999			STAT2	Lau et al., 2003
		Chen et al., 2006			Gal4	Koh et al., 1998	Yeast
		Chen & Roeder, 2007			RXR	Park et al., 2003	Drosophila
		Kim et al., 2008			p65	van Essen et al., 2009
	HNF4	Malik et al., 2002		MED19	REST	Ding et al., 2009
	p53	Ito et al., 1999		MED21	TRα	Nevado et al., 2004	Yeast
		Frade et al., 2000			Tup1	Hallberg et al., 2006	Yeast
		Drane et al., 1997		MED22	GCN4	Swanson et al., 2003	Yeast
		Meyer et al., 2010		MED23	C/EBPβ	Mo et al., 2004
	BRCA1	Wada et al., 2004			ESX	Asada et al., 2002
	NR4A	Wansa & Muscat, 2005				Shimogawa et al., 2004
	FXR	Pineda Torra et al., 2004			E1a	Stevens et al., 2002
	RORα	Atkins et al., 1999				Wang & Berk, 2002
	AHR	Wang et al., 2004b				Boyer et al., 1999
	GATA-1	Stumpf et al., 2006			ELK1	Asada et al., 2002
		Crawford et al., 2002				Stevens et al., 2002
	Pit-1	Gordon et al., 2006				Cantin et al., 2003
	GATA-2	Gordon et al., 2006			Dif	Kim et al., 2004	Drosophila
	GABPα	Udayakumar et al., 2006			HSF	Kim et al., 2004	Drosophila
	MYC	Liu et al., 2008			IRF7	Griffiths et al., 2013
	POU1F1	Gordon et al., 2006		MED24	TR	Yuan et al., 1998
	14-3-3	Zilliacus et al., 2001		MED25	VP16	Mittler et al., 2003
	PGC-1α	Wallberg et al., 2003				Yang et al., 2004
	C/EBPβ	Li et al., 2008				Park et al., 2000
MED2	Gcn4	Zhang et al., 2004	yeast		RAR	Lee et al., 2007
		Natarajan et al., 1999	yeast		HNF4α	Rana et al., 2011
MED3	Gcn4	Zhang et al., 2004	yeast		ERM	Verger et al., 2013
MED8	Ace2	Mehta et al., 2009	yeast		SOX9	Nakamura et al., 2011
MED12	RTA	Gwack et al., 2003			ATF6α	Sela et al., 2013
	SOX9	Zhou et al., 2002		MED28	GRB2	Wiederhold et al., 2004
		Rau et al., 2006	Zebrafish	MED29	DSX	Sato et al., 2003a
	NANOG	Tutter et al., 2009				Garrett-Engele et al., 2002	Drosophila
	CTNNB1	Kim et al., 2006a		MED31	HSF	Kim et al., 2004	Drosophila
	REST	Ding et al., 2008		CDK8	MYC	Eberhardy & Farnham, 2002
	G9a	Ding et al., 2008			Hsf	Park et al., 2001	Drosophila
	Gli3	Zhou et al., 2006
	β-catenin	Kim et al., 2006a
	AICD	Xu et al., 2011b
MED14	GR	Hittelman et al., 1999
		Chen et al., 2006
	STAT2	Lau et al., 2003
	HNF4	Malik et al., 2002
	ERα	Lee et al., 2005a
	PPARγ	Grontved et al., 2010
	SREBP-1a	Toth et al., 2004

*All interactions were identified in mammals unless otherwise noted. References that validate the interaction are also listed.

Figure 3. Cryo-EM structure of yeast Mediator. The EM data reveal structural flexibility (Cai et al., 2009) that can even be inferred from the 3D reconstruction, with its large domains connected by narrow linkers. Note also the extensive surface area, due to channels and cavities in the structure. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 4. Human Mediator undergoes a structural shift upon binding the pol II CTD. EM structures of unliganded Mediator (left) and CTD-bound Mediator (right) are shown. Note the CTD-Mediator sample is bound to native, full-length (52 YSPTSPS heptad repeat) mammalian CTD (Naar et al., 2002). (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 5. Schematic outlining human Mediator structural changes induced by pol II-TFIIF binding. Two different views (front and side 1) are shown. Three Mediator domains (labeled 1, 2 and 3) are highlighted in the side 1 view and their putative locations are indicated following pol II-TFIIF binding. Note that structural re-organization occurs throughout the Mediator complex upon pol II-TFIIF binding, including the distal “leg/tail” domain (boxed), which represents a site for CDK8 module binding (Bernecky et al., 2011). The “Mediator only” and the “Mediator–pol II–TFIIF” structures each are bound to the activation domain of VP16. Pol II is shown in red (PDB 1Y1V). (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 6. CDK8 module–Mediator binding appears to occlude pol II–Mediator binding by an allosteric mechanism. EM structures of Mediator and CDK8-Mediator (both bound to the activation domain of VP16) are shown (Taatjes et al., 2002). The lower panel shows “bottom” views of each complex, with the dashed line on Mediator representing the surface that appears to make direct contacts with pol II (Bernecky et al., 2011). The bracket shows the general region occupied by pol II upon binding human Mediator, and the corresponding position in the CDK8-Mediator complex. The structural difference in this bracketed region may reflect a structural change important to prevent pol II (and pol II CTD) binding to CDK8-Mediator. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 7. Distinct modes of CDK8 module (CKM) binding to yeast Mediator. EM structure at left shows a single CKM-Mediator interaction via Med13, whereas the structure on the right shows a more extensive interface that also involves Cdk8 (Tsai et al., 2013). Scale bar: 100 Å. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 8. TF binding induces structural shifts throughout the human Mediator complex. Similar views of EM structures of Mediator without a TF bound (top), or bound to the activation domain of SREBP or VP16 are shown (Taatjes et al., 2002). Note that structural changes appear to propagate throughout the complex, and that structural changes are distinct for each TF. Localization of the VP16 (X) and SREBP (+) binding sites are shown. Scale bar: 100 Å. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 9. A working model for Mediator and CDK8-Mediator regulation of transcription initiation and elongation. This model depicts four functionally distinct structural states (I–IV) for Mediator. We hypothesize that different Mediator surfaces will be exposed in each state, which may help coordinate timing of factor recruitment to the promoter, in accordance with requirements for various stages of transcription. According to this model, state I and state II are compatible with pre-initiation events, state III represents transcription initiation (possibly including paused pol II), and state IV represents an elongation-competent structure. In state I, Mediator is not bound to a TF; Mediator is capable of binding pol II in this structural state, but pol II will be inactive or minimally active (i.e. basal transcription). TF binding (e.g. VP16) causes a structural shift to state II. Mediator is also capable of binding pol II in this conformational state, with the potential to direct high levels of “activated” transcription. This structural state might also coordinate timing of other Mediator-cofactor interactions at the promoter that could regulate subsequent stages of transcription (Ebmeier & Taatjes, 2010). If pol II binds the TF-Mediator complex, this leads to structural state III. This structural state may be compatible with activated transcription, perhaps by promoting synergy among PIC factors (e.g. TFIIH, TFIID and TFIIB) that assemble around the Mediator–pol II complex. Note that in this structural state, the CDK8 module is incapable of binding Mediator. Upon transcription initiation and pol II transition to productive elongation, pol II breaks contacts with Mediator; Mediator structure transitions back to state II (TF bound, but no pol II). The CDK8 module is able to bind Mediator in this structural state. If the CDK8 module binds Mediator, Mediator adopts structural state IV. This structural state (i.e. CDK8-Mediator) does not allow pol II binding. Thus, the CDK8-Mediator complex prevents a second pol II enzyme from immediately re-engaging the promoter, which might otherwise cause defects in mRNA processing or defects during initiation by this second pol II. Furthermore, the CDK8-Mediator complex could help assemble and/or regulate elongation factors, thereby influencing ongoing elongation events. The ability of CDK8-Mediator or core Mediator (i.e. Mediator containing MED26) to positively influence pol II elongation has been documented by several groups (Donner et al., 2010; Galbraith et al., 2013; Takahashi et al., 2011). Yet Mediator and other PIC components remain at the promoter following pol II promoter escape, leaving a “scaffold” complex (Yudkovsky et al., 2000). These apparently contradictory findings are reconciled by growing evidence that elongating pol II complexes are likely stationary, and that rather than moving directionally along DNA, pol II instead “reels in” the DNA template (Papantonis et al., 2010). This has already been demonstrated for bacterial polymerases (Kapanidis et al., 2006; Revyakin et al., 2006), and DNA polymerases work in much the same way (Anachkova et al., 2005). Stationary, elongating pol II complexes could be juxtaposed with promoter-bound factors, facilitating Mediator- or CDK8-Mediator-dependent regulation of pol II elongation. We emphasize that this is a model, and that many aspects remain to be rigorously tested. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 10. A structural model of the human PIC. The cryo-EM structure of human pol II, TBP, TFIIA, TFIIB, TFIIE and TFIIF bound to promoter DNA (closed complex (He et al., 2013)) was docked into the cryo-EM map of human Mediator–pol II–TFIIF (Bernecky et al., 2011). In the docked structures, the Mediator-pol II-TFIIF cryo-EM map is shown in blue mesh, whereas the color-coding for the other PIC factors is indicated. For reference, the same orientation of the Mediator–pol II–TFIIF structure alone is shown in solid blue. Addition of TFIIH (pink) to the model blocks details of the structure, therefore, we show the model with and without TFIIH (below). The view without TFIIH also indicates an open region for its assembly into the PIC. Note that some structural reorganization occurs within the PIC upon TFIIH binding (He et al., 2013). To generate the model, the docked pol II crystal structure was used as a reference to align both cryo-EM maps in Chimera. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 11. A common structural feature among TF-bound human Mediator complexes. EM structures are shown for Mediator bound to different TF activation domains and compared with Mediator that is not TF-bound (inset). A shared structural feature is a “pocket” (green arrow) and the surfaces corresponding to probable sites of pol II interaction are highlighted with the dashed yellow line. Note these features are absent from the unliganded Mediator structure. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 12. A model for TF-dependent “post-recruitment” activation of a fully assembled but latent PIC. In the absence of a key TF, a PIC may occupy the promoter, but pol II remains largely inactive or paused. Upon TF binding to the promoter, it interacts with Mediator and triggers a structural shift in the complex, which activates the PIC and allows pol II to escape the promoter region and transition to a productively elongating state. Part of this process could involve functional synergy between Mediator and pausing/elongation factors such as DSIF, Gdown1/POLR2M or the SEC. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 13. Gdown1/POLR2M, TFIIF and pol II each converge on the same structural interface of Mediator. At left is shown a “bottom” view of the VP16-Mediator complex (Taatjes et al., 2002). A pol II interaction surface is highlighted by the yellow dashed line. This distinctive interaction surface forms upon TF binding (see Figure 11). At center is a “front” view of the Mediator complex, with pol II (red ribbon; PDB 1Y1V) oriented consistent with its bound state orientation in the VP16-Mediator-pol II-TFIIF assembly (Bernecky et al., 2011), shown at right. Highlighted at right is a general location for Gdown1 binding to pol II, based upon cryo-EM data (Wu et al., 2012), as well as the approximate location of TFIIF, based upon crosslinking-MS data and cryo-EM data (Chen et al., 2010b; Eichner et al., 2010; He et al., 2013). The cryo-EM map for the VP16-Mediator-pol II-TFIIF assembly is shown in blue mesh, with pol II docked as described (Bernecky et al., 2011). (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 14. A simple schematic illustrating enhancer-promoter communication via Mediator. Mediator can bind simultaneously to enhancer-bound TFs and the PIC, including pol II. (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Figure 15. EM structures of the human (A) and yeast (B) CDK8 module. The structures are distinct and not shown in similar orientations. Structural distinctions may derive from sequence differences, in particular, the much larger sizes for human MED12 and MED13. MED13 forms an extended hook-like structure in each, and this subunit has been shown to contact core Mediator (Knuesel et al., 2009a; Tsai et al., 2013). Whereas the general location of MED13 was determined for the human CDK8 module, localization of each subunit was determined for the yeast structure with antibody labeling (C). (see colour version of this figure online at www.informahealthcare.com/bmgwww.informahealthcare.com/bmg).

Table 4. Current known CDK8 kinase substrates.

Protein	Reference	Protein	Reference
Notch ICD	Fryer et al., 2004	Msn2	Chi et al., 2001
SMAD1	Alarcon et al., 2009	Gcn4	Chi et al., 2001
SMAD3	Alarcon et al., 2009	Gal4	Hirst et al., 1999
SREBP	Zhao et al., 2012	Ste12	Nelson et al., 2003
E2F1	Morris et al., 2008	Phd1	Raithatha et al., 2012
STAT1	Bancerek et al., 2013	Sip4	Vincent et al., 2001
histone H3	Meyer et al., 2008	Fkh2	Szilagyi et al., 2012
CCNH	Akoulitchev et al., 2000	Med2	Liu et al., 2004
PC4	Gu et al., 1999	Taf2	Liu et al., 2004
CDK8	Knuesel et al., 2009b	Bdf1	Liu et al., 2004
MED13	Knuesel et al., 2009b

Note that each substrate can be considered chromatin associated. DNA-binding TFs are shown in bold font. Human CDK8 kinase substrates are shown on the left and yeast Cdk8 (srb10) substrates are shown on the right.

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